RESUMEN
Adherence to HIV pre-exposure prophylaxis (PrEP) study drug is critical for safety, tolerability, and efficacy trials, and may be affected by how adherence is communicated by the study staff to trial participants. Increasingly, clinical trials investigating PrEP are creating and implementing 'participant-centered' approaches that discuss potential non-adherence neutrally (without negative judgement) and support efforts to adhere versus insisting on perfect adherence. In the HPTN069/ACTG A5305 study, we evaluated participant experiences of potentially negative adherence-related interactions with study teams using ten items to characterize the frequency of such experiences. We related these individual items and a combined set of seven negative experience items (total negative experience score) to drug concentrations (detectable or consistent with daily-dosing). The exploratory analyses used logistic regression for each experience item on the full sample and disaggregated by sex. Several experiences were related to drug detection and to daily-dosing, although more so for participants identifying as men than women. Total negative experience scores associated with not having detection drug concentrations for the full sample, and remained significant even when controlling for sex, age, and race. Daily dosing was associated with total negative experience score for men in the sample. Additional investigations into adherence-related interactions with study teams that are most problematic or helpful in general and uniquely for men and women are warranted.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Femenino , Humanos , Masculino , Fármacos Anti-VIH/uso terapéutico , Emtricitabina , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Homosexualidad Masculina , Cumplimiento de la Medicación , Autoinforme , Ensayos Clínicos como AsuntoRESUMEN
Despite the availability of 16 antiretroviral drugs approved for the treatment of HIV infection, current combination regimens present challenges. Newer antiretroviral drugs are needed to improve convenience, reduce toxicity and, of particular importance, to provide antiretroviral activity against viral strains resistant to the currently available antiretroviral agents. Candidate drugs with novel properties are in development in the two currently available drug classes: HIV reverse transcriptase inhibitors (nucleoside analogs, non-nucleoside analogs and nucleotide analogs) and HIV protease inhibitors (PI). Investigational nucleoside analog reverse transcriptase inhibitors (nRTI) include emtricitabine (FTC) and amdoxovir (DAPD), and investigational non-nucleoside reverse transcriptase inhibitors (NNRTI) include DPC 083 and TMC 125. New protease inhibitors under investigation include atazanavir (BMS-232 632), tipranavir, and TMC 114. In addition, newer agents with novel mechanisms of action such as HIV entry inhibitors (that inhibit the three steps of HIV entry: CD4 attachment, chemokine receptor binding and membrane fusion) and HIV integrase inhibitors are under investigation. Investigational entry inhibitors include PRO 542 (a CD4 attachment inhibitor), Schering C (a chemokine receptor inhibitor), enfuvirtide (T-20) and T-1249, inhibitors of membrane fusion. Investigational HIV integrase inhibitors include S-1360. Continued progress in the treatment of HIV disease will result from the development of new antiretroviral drugs.
Asunto(s)
Fármacos Anti-VIH/farmacología , Inhibidores de Fusión de VIH/farmacología , Inhibidores de Integrasa VIH/farmacología , Inhibidores de la Proteasa del VIH/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/química , Diseño de Fármacos , Quimioterapia Combinada , Inhibidores de Fusión de VIH/química , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Inhibidores de Integrasa VIH/química , Inhibidores de la Proteasa del VIH/química , VIH-1/efectos de los fármacos , Humanos , Inhibidores de la Transcriptasa Inversa/químicaAsunto(s)
Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/administración & dosificación , Selección de Paciente , Adulto , Causas de Muerte , ADN Viral/efectos de los fármacos , ADN Viral/genética , Esquema de Medicación , Farmacorresistencia Viral/genética , Quimioterapia Combinada , Infecciones por VIH/epidemiología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/genética , Humanos , Masculino , Morbilidad , Guías de Práctica Clínica como Asunto , Inhibidores de la Transcriptasa Inversa , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
UNLABELLED: The effect of ritonavir 400 mg/saquinavir 400 mg twice daily on the stereoselective pharmacokinetics of methadone was examined in 12 HIV-infected, methadone-using study subjects. DESIGN: A 24-hour methadone pharmacokinetic study was performed before antiretroviral therapy was begun and after 15 days of therapy. Methadone concentration was measured by a chiral plasma assay because the drug is administered as a racemic mixture of R- and S-methadone, but only the R-isomer is active. Both changes in plasma protein binding and changes in objective and subjective opioid effect were monitored. RESULTS: Ritonavir/saquinavir administration was associated with 40% decrease in total S-methadone AUC0-24hr and 32% decrease in R-methadone area under the curve (AUC)0-24hr, and both changes were statistically significant (p =.001 for both). When AUC was corrected for the changes in protein binding induced by ritonavir/saquinavir, R-methadone free AUC0-24hr decreased 19.6% whereas the S-methadone decreased 24.6%, neither of these changes was statistically significant (p =.129 and p =.0537, respectively). This change in methadone exposure was not associated with any evidence of withdrawal from narcotics and no modification of methadone dose was required. CONCLUSIONS: Our data indicate that ritonavir/saquinavir administration is associated with induction of metabolism of methadone but this is greater for the inactive S-methadone. However, approximately 37% of the decrease in the total R-methadone exposure can be explained by protein binding displacement. Ritonavir/saquinavir can be used in HIV-infected people taking methadone without routine dose adjustments.
Asunto(s)
Inhibidores de la Proteasa del VIH/administración & dosificación , Metadona/farmacocinética , Narcóticos/farmacocinética , Ritonavir/administración & dosificación , Saquinavir/administración & dosificación , Adulto , Interacciones Farmacológicas , Femenino , Infecciones por VIH/tratamiento farmacológico , VIH-1/fisiología , Humanos , Masculino , Metadona/uso terapéutico , Persona de Mediana Edad , Narcóticos/uso terapéutico , Ritonavir/sangre , Saquinavir/sangre , Estereoisomerismo , Abuso de Sustancias por Vía Intravenosa/complicaciones , Abuso de Sustancias por Vía Intravenosa/rehabilitaciónRESUMEN
Early identification of treatment failure among human immunodeficiency virus (HIV) type 1--infected patients receiving antiretroviral therapy could enable clinicians to modify inadequate regimens and to improve treatment response. Clinical definitions of treatment failure, however, may not be ideally suited for this purpose. This study empirically characterizes the patterns of HIV-1 RNA response to antiretroviral therapy in patients in 4 AIDS clinical trials. The approach assumed 2 patterns of HIV-1 response: "on track," for eventual suppression to HIV-1 RNA levels below the limit of quantification, and "off track," for deviation from this response. The results of this on- or off-track classification generally agreed with the protocol-defined outcomes of virologic success and failure, thus validating these commonly used definitions. Overall, only a minority of patients went off track because of suboptimal HIV-1 RNA response by the first follow-up visit. Most patients who went off track did so at later time points and had sharp unexpected rebounds without prior indication of a suboptimal response.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Terapia Antirretroviral Altamente Activa , Ensayos Clínicos como Asunto , VIH-1/genética , Humanos , Cinética , ARN Viral/sangre , Estudios Retrospectivos , Insuficiencia del TratamientoRESUMEN
Residual viral replication persists in a significant proportion of human immunodeficiency virus (HIV)-infected patients receiving potent antiretroviral therapy. To determine the source of this virus, levels of HIV RNA and DNA from lymphoid tissues and levels of viral RNA in serum, cerebrospinal fluid (CSF), and genital secretions in 28 patients treated for < or =2.5 years with indinavir, zidovudine, and lamivudine were examined. Both HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF samples after 2 years of treatment. HIV envelope sequence data from plasma and lymph nodes from 4 patients demonstrated sequence divergence, which suggests varying degrees of residual viral replication in 3 and absence in 1 patient. In patients receiving potent antiretroviral therapy, the greatest virus burden may continue to be in lymphoid tissues rather than in central nervous system or genitourinary compartments.
Asunto(s)
ADN Viral/análisis , Genitales/virología , Infecciones por VIH/virología , VIH-1/genética , Ganglios Linfáticos/virología , ARN Viral/análisis , Estudios de Cohortes , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/líquido cefalorraquídeo , Infecciones por VIH/tratamiento farmacológico , VIH-1/aislamiento & purificación , Humanos , Indinavir/uso terapéutico , Lamivudine/uso terapéutico , Estudios Longitudinales , Masculino , Datos de Secuencia Molecular , ARN Viral/sangre , ARN Viral/líquido cefalorraquídeo , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Tiempo , Carga Viral , Viremia , Replicación Viral/efectos de los fármacos , Zidovudina/uso terapéuticoRESUMEN
This prospective, multicenter, open-label study was designed to determine the antiretroviral activity and safety of a 4-drug regimen: 1000 mg indinavir every 8 h with 200 mg nevirapine, 40 mg stavudine, and 150 mg lamivudine, each given twice daily in amprenavir-experienced subjects. The primary end points of the study were the human immunodeficiency virus (HIV) RNA level and CD4 cell count responses. Fifty-six subjects were enrolled and were changed from amprenavir-containing regimens to the 4-drug regimen. Overall, at week 48, 33 (59%) of 56 subjects had HIV RNA levels <500 copies/mL (intent-to-treat analysis, where missing values equal > or =500 copies/mL) and CD4 cell counts increased by 94 cells/mm(3) from baseline. Subjects who had previously taken amprenavir combination therapy were more likely to experience virologic failure than those who had taken amprenavir monotherapy (odds ratio, 7.7; P=.0012). In this study, most subjects who had taken amprenavir-based regimens and who changed to a 4-drug regimen achieved subsequent durable virologic suppression.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , ARN Viral/análisis , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Recuento de Linfocito CD4 , Carbamatos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Femenino , Furanos , Infecciones por VIH/inmunología , Humanos , Indinavir/administración & dosificación , Indinavir/uso terapéutico , Lamivudine/administración & dosificación , Lamivudine/uso terapéutico , Masculino , Nevirapina/administración & dosificación , Nevirapina/uso terapéutico , Oportunidad Relativa , Estudios Prospectivos , Seguridad , Estavudina/administración & dosificación , Estavudina/uso terapéutico , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , Factores de Tiempo , Resultado del Tratamiento , Carga ViralRESUMEN
OBJECTIVE: To evaluate the safety and antiviral activity of different dose levels of the HIV protease inhibitor ABT-378 combined with low-dose ritonavir, plus stavudine and lamivudine in antiretroviral-naive individuals. DESIGN: Prospective, randomized, double-blind, multicenter. METHODS: Eligible patients with plasma HIV-1 RNA > 5000 copies/ml received ABT-378 200 or 400 mg with ritonavir 100 mg every 12 h; after 3 weeks stavudine 40 mg and lamivudine 150 mg every 12 h were added (group I, n = 32). A second group initiated treatment with ABT-378 400 mg and ritonavir 100 or 200 mg plus stavudine and lamivudine every 12 h (group II, n = 68). RESULTS: Mean baseline HIV-1 RNA was 4.9 log10 copies/ml in both groups and CD4 cell count was 398 x 10(6)/l and 310 x 10(6)/l in Groups I and II respectively. In the intent-to-treat (ITT; missing value = failure) analysis at 48 weeks, HIV-1 RNA was < 400 copies/ml for 91% (< 50 copies/ml, 75%) and 82% (< 50 copies/ml, 79%) of patients in groups I and II respectively. Mean steady-state ABT-378 trough concentrations exceeded the wild-type HIV-1 EC50 (effective concentration to inhibit 50%) by 50-100-fold. The most common adverse events were abnormal stools, diarrhea and nausea. No patient discontinued before 48 weeks because of treatment-related toxicity or virologic rebound. CONCLUSIONS: ABT-378 is a potent, well-tolerated protease inhibitor. The activity and durable suppression of HIV-1 observed in this study is probably attributable to the observed tolerability profile and the achievement of high ABT-378 plasma concentrations.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/efectos de los fármacos , Lamivudine/uso terapéutico , Pirimidinonas/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Ritonavir/uso terapéutico , Estavudina/uso terapéutico , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacocinética , Recuento de Linfocito CD4 , Quimioterapia Combinada , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/fisiopatología , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Lamivudine/efectos adversos , Lamivudine/farmacocinética , Lopinavir , Masculino , Pirimidinonas/efectos adversos , Pirimidinonas/farmacocinética , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/farmacocinética , Ritonavir/efectos adversos , Ritonavir/farmacocinética , Estavudina/efectos adversos , Estavudina/farmacocinética , Carga ViralRESUMEN
This study compared antiretroviral activity among 6 "salvage" therapy regimens. The study was a prospective, randomized, 2x3 factorial, multicenter study of the AIDS Clinical Trials Group. The study enrolled 277 human immunodeficiency virus (HIV)-infected patients naive to nonnucleoside analogues who had taken indinavir >6 months. The patients had 2000-200,000 HIV RNA copies/mL. Patients received saquinavir with ritonavir or nelfinavir together with delavirdine and/or adefovir and were followed for safety and antiretroviral response between baseline and week 16. At week 16, 30% (77/254) of patients had
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Organofosfonatos , Adenina/administración & dosificación , Adenina/análogos & derivados , Adulto , Fármacos Anti-VIH/efectos adversos , Recuento de Linfocito CD4 , Delavirdina/administración & dosificación , Método Doble Ciego , Quimioterapia Combinada , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Masculino , Nelfinavir/administración & dosificación , Estudios Prospectivos , ARN Viral/análisis , Ritonavir/administración & dosificación , Saquinavir/administración & dosificaciónRESUMEN
BACKGROUND: No clinical trial results directly comparing two nucleoside analog pairs in a drug regimen for HIV that includes a protease inhibitor are available. OBJECTIVE: To compare the safety and efficacy of stavudine (d4T) + lamivudine (3TC) with zidovudine (ZDV) + 3TC, each in combination with indinavir (IDV). DESIGN: Randomized, open-label, multi-center. SETTING: Fifteen HIV clinical research centers. PATIENTS: Two-hundred and four antiretroviral-naive HIV-1-infected-patients with CD4 cell counts > or = 200 x 10(6)/l and HIV-1 RNA > or = 10,000 copies/ml (bDNA assay), modified to 5000 copies/ml. INTERVENTION: d4T 40 mg twice a day, 3TC 150 mg twice a day plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h (modified to 300 mg every 12 h) plus 3TC and IDV. MEASUREMENTS: Primary endpoint: plasma HIV-1 RNA < 500 copies/ml. Additional endpoints: HIV-1 RNA < or = 50 copies/ml; change from baseline in HIV-1 RNA and CD4 cell counts; safety and adverse events. RESULTS: For HIV-1 RNA, 62% of patients on d4T + 3TC + IDV and 54% of patients on ZDV + 3TC + IDV had < 500 copies/ml HIV RNA at weeks 40 through 48 [90% confidence interval, -0.204 to 0.036; P= 0.213], with 49% and 47% respectively achieving < or = 50 copies/ml at 48 weeks (90% CI, -0.134 to 0.096; P = 0.834). Median change in CD4 cell counts at 48 weeks was +227 x 10(6)/l and +198 x 10(6)/l for the d4T- and ZDV-containing arms, respectively. The median time-weighted average change from baseline in CD4 cell counts was significantly greater at 48 weeks in the d4T-containing arm (142 x 10(6)/l versus 110 x 10(6)/l; P = 0.033). Serious adverse events were not significantly different between treatment arms, but there were significant differences for frequency of adverse events of all severity with increased nausea and vomiting in the ZDV-containing arm, and increased diarrhea and rash in the d4T-containing arm. CONCLUSIONS: These results support the choice of d4T + 3TC as a nucleoside analog pair in combination with a protease inhibitor in an initial HIV treatment regimen.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1 , Indinavir/uso terapéutico , Lamivudine/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Estavudina/uso terapéutico , Zidovudina/uso terapéutico , Fármacos Anti-VIH/efectos adversos , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Femenino , Estudios de Seguimiento , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/efectos adversos , VIH-1/genética , Humanos , Indinavir/efectos adversos , Lamivudine/efectos adversos , Masculino , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/efectos adversos , Estavudina/efectos adversos , Timidina/análogos & derivados , Zidovudina/efectos adversosRESUMEN
BACKGROUND: Antiretroviral regimens containing HIV protease inhibitors suppress viremia in HIV-infected patients, but the durability of this effect is not known. OBJECTIVE: To describe the 3-year follow-up of patients randomly assigned to receive indinavir, zidovudine, and lamivudine in an ongoing clinical trial. DESIGN: Open-label extension of a randomized, double-blind study. SETTING: Four clinical research units. PATIENTS: 33 HIV-infected, zidovudine-experienced patients with serum HIV RNA levels of at least 20,000 copies/mL and CD4 counts ranging from 50 to 400 cells/mm3. INTERVENTION: Indinavir, zidovudine, and lamivudine. MEASUREMENTS: Safety assessments, HIV RNA levels, CD4 cell counts, and genotypic analyses. RESULTS: After 3 years of follow-up, 21 of 31 contributing patients (68% [95% CI, 49% to 83%]) had serum viral load levels less than 500 copies/mL. Twenty of 31 (65% [CI, 45% to 80%]) had levels less than 50 copies/mL. The median increase in CD4 count from baseline was 230 cells/mm3 (interquartile range, 150 to 316 cells/mm3). Nephrolithiasis occurred in 12 of 33 patients (36%). CONCLUSION: A three-drug regimen of indinavir, zidovudine, and lamivudine suppressed viremia in two thirds of patients for at least 3 years.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Indinavir/uso terapéutico , Lamivudine/uso terapéutico , Viremia/tratamiento farmacológico , Zidovudina/uso terapéutico , Adulto , Fármacos Anti-VIH/efectos adversos , Recuento de Linfocito CD4 , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Genotipo , VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Indinavir/efectos adversos , Cálculos Renales/inducido químicamente , Lamivudine/efectos adversos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Carga Viral , Zidovudina/efectos adversosAsunto(s)
Antivirales/uso terapéutico , Infecciones Oportunistas/tratamiento farmacológico , Infecciones por Retroviridae/tratamiento farmacológico , Adolescente , Adulto , Fármacos Anti-VIH/uso terapéutico , Antivirales/economía , Farmacorresistencia Microbiana/genética , Quimioterapia Combinada , Femenino , Genotipo , Guías como Asunto , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/transmisión , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Lactante , Recién Nacido , Masculino , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/prevención & control , Fenotipo , Embarazo , Retroviridae/efectos de los fármacos , Retroviridae/genética , Infecciones por Retroviridae/complicaciones , Infecciones por Retroviridae/prevención & control , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Factores de Riesgo , Factores Sexuales , Sobreinfección/tratamiento farmacológico , Carga ViralRESUMEN
Clinical cohort studies suggest that as many as 60% of patients experience virologic failure of a first-line antiretroviral regimen. Second-line and rescue (or salvage) regimens have a poorer success record: Most studies presented to date show a short-term virologic response rate of only approximately 30% in treatment-experienced individuals. That rate will improve with better understanding of what causes initial virologic failure, continued development of new antiretroviral agents (including drugs with new mechanisms of action) and new treatment strategies (including dual-protease inhibitor regimens), and more widespread use of resistance testing. Further clinical research is needed to improve salvage options, and physicians should consider enrolling treatment-experienced patients in clinical trials.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por Retroviridae/tratamiento farmacológico , Recuento de Linfocito CD4 , Carbamatos , Didesoxinucleósidos/uso terapéutico , Quimioterapia Combinada , Furanos , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Indinavir/farmacología , Indinavir/uso terapéutico , Lopinavir , Pruebas de Sensibilidad Microbiana , Mutación , Nelfinavir/uso terapéutico , Guías de Práctica Clínica como Asunto , Pirimidinonas/química , Pirimidinonas/farmacología , Pirimidinonas/uso terapéutico , Retroviridae/efectos de los fármacos , Retroviridae/genética , Retroviridae/aislamiento & purificación , Infecciones por Retroviridae/inmunología , Infecciones por Retroviridae/virología , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Sulfonamidas/uso terapéutico , Factores de Tiempo , Insuficiencia del Tratamiento , Carga ViralRESUMEN
Antiretroviral therapy may lead to decreased shedding of human immunodeficiency virus type 1 (HIV-1) in genital secretions. Thirty men, 19 receiving amprenavir and 11 receiving amprenavir, zidovudine, and lamivudine, donated blood and semen while undergoing treatment, to evaluate the effects of these medications on HIV-1 shedding in semen. Before therapy, 4 men had HIV-1 RNA levels in seminal plasma >6.0 log10 (1 million) copies/mL, markedly higher than levels in blood plasma. Most men (77%) had HIV-1 RNA levels in seminal plasma below the limit of quantification during therapy. Amprenavir alone suppressed HIV-1 RNA levels to <400 copies/mL in seminal plasma in the majority of patients, the first direct demonstration of the antiretroviral effects of a protease inhibitor in the male genital tract. However, 8 men (27%) had measurable HIV-1 in seminal plasma at their last study visit, 4 with increasing levels. Persistent replication of HIV in the genital tract may have implications for the selection of resistant virus and sexual transmission of HIV-1.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/aislamiento & purificación , Lamivudine/uso terapéutico , Semen/virología , Sulfonamidas/uso terapéutico , Zidovudina/uso terapéutico , Adulto , Carbamatos , Método Doble Ciego , Quimioterapia Combinada , Furanos , Infecciones por VIH/sangre , VIH-1/fisiología , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/análisis , ARN Viral/sangre , Análisis de Regresión , Esparcimiento de Virus/efectos de los fármacosRESUMEN
OBJECTIVE: To evaluate the steady state concentrations of saquinavir, ritonavir, nelfinavir, delavirdine, and adefovir in six different three- and four-drug combination regimens. DESIGN: Randomized, partially double-blinded, multicenter study in a population of indinavir-experienced subjects with virologic failure. The first seven subjects enrolled in each of the six treatment arms from 10 participating sites were entered into this pharmacokinetic evaluation. SETTING: Multicenter study of the AIDS Clinical Trials Group (ACTG). PATIENTS: HIV-infected subjects. INTERVENTIONS: A 12-hour pharmacokinetic study was conducted after 2 weeks of drug administration. MAIN OUTCOME MEASURES: Area under the concentration-time curve with statistical comparisons to evaluate the effect of the second protease inhibitor and the effect of the non-protease inhibitors. RESULTS: There was no difference in saquinavir concentrations according to whether the second protease inhibitor was ritonavir or nelfinavir. Saquinavir concentrations in the groups receiving the combination of delavirdine plus adefovir dipivoxil were reduced by approximately 50% compared with those receiving delavirdine. Delavirdine concentrations were reduced by approximately 50%, in the delavirdine plus adefovir dipivoxil arms compared with the delavirdine arms. CONCLUSIONS: Saquinavir concentrations were significantly lower in the arms containing the combination of delavirdine and adefovir dipivoxil compared with the arms containing delavirdine. Delavirdine concentrations were significantly lower when coadministered with adefovir dipivoxil. These drug-drug interactions were not expected, the mechanism(s) is (are) not clear, and additional studies are warranted. This study illustrates the need to understand more fully the pharmacokinetic characteristics of complex combination antiretroviral regimens prior to use in patient management.
Asunto(s)
Adenina/farmacocinética , Fármacos Anti-VIH/farmacocinética , Delavirdina/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Organofosfonatos , Inhibidores de la Transcriptasa Inversa/farmacocinética , Adenina/análogos & derivados , Adenina/uso terapéutico , Adulto , Fármacos Anti-VIH/uso terapéutico , Delavirdina/uso terapéutico , Método Doble Ciego , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Infecciones por VIH/metabolismo , Humanos , Masculino , Nelfinavir/farmacocinética , Nelfinavir/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Ritonavir/farmacocinética , Ritonavir/uso terapéutico , Saquinavir/farmacocinética , Saquinavir/uso terapéuticoRESUMEN
Amprenavir is a human immunodeficiency virus (HIV) protease inhibitor with a favorable pharmacokinetic profile and good in vitro activity. Ninety-two lamivudine- and protease inhibitor-naive individuals with >/=50 CD4 cells/mm3 and >/=5000 HIV RNA copies/mL were assigned amprenavir (1200 mg) alone or with zidovudine (300 mg) plus lamivudine (150 mg), all given every 12 h. After a median follow-up of 88 days, the findings of a planned interim review resulted in termination of the amprenavir monotherapy arm. Among 85 subjects with confirmed plasma HIV RNA determination, 15 of 42 monotherapy versus 1 of 43 triple-therapy subjects had an HIV RNA increase above baseline or 1 log10 above nadir (P=.0001). For subjects taking triple therapy at 24 weeks, the median decrease in HIV RNA was 2.04 log10 copies/mL, and 17 (63%) of 27 evaluable subjects had <500 HIV RNA copies/mL. Treatment with amprenavir, zidovudine, and lamivudine together reduced the levels of HIV RNA significantly more than did amprenavir monotherapy.
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Lamivudine/administración & dosificación , Sulfonamidas/uso terapéutico , Zidovudina/administración & dosificación , Adulto , Recuento de Linfocito CD4 , Carbamatos , Método Doble Ciego , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Furanos , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Sulfonamidas/administración & dosificaciónRESUMEN
BACKGROUND: Hypericin, the active compound in St. John's Wort, has antiretroviral activity in vitro. Many HIV-infected persons use St. John's wort. OBJECTIVE: To evaluate the safety and antiretroviral activity of hypericin in HIV-infected patients. DESIGN: Phase I study. SETTING: Four clinical research units. PATIENTS: 30 HIV-infected patients with CD4 counts less than 350 cells/mm3. INTERVENTION: Intravenous hypericin, 0.25 or 0.5 mg/kg of body weight twice weekly or 0.25 mg/kg three times weekly, or oral hypericin, 0.5 mg/kg daily. MEASUREMENTS: Safety was assessed at weekly visits. Antiretroviral activity was assessed by changes in HIV p24 antigen level, HIV titer, HIV RNA copies, and CD4 cell counts. RESULTS: Of the 30 patients who were enrolled, 16 discontinued treatment early because of toxic effects. Severe cutaneous phototoxicity was observed in 11 of 23 (48% [95% CI, 27% to 69%]) evaluable patients, and dose escalation could not be completed. Virologic markers and CD4 cell count did not significantly change. CONCLUSIONS: Hypericin caused significant phototoxicity and had no antiretroviral activity in the limited number of patients studied.
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Perileno/análogos & derivados , Administración Oral , Adulto , Antracenos , Fármacos Anti-VIH/efectos adversos , Recuento de Linfocito CD4 , Dermatitis Fototóxica/etiología , Femenino , Estudios de Seguimiento , Proteína p24 del Núcleo del VIH/sangre , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Inyecciones Intravenosas , Masculino , Perileno/efectos adversos , Perileno/uso terapéutico , ARN Viral/sangre , Estadísticas no Paramétricas , Carga ViralRESUMEN
AIDS: The current guidelines for HIV therapy are two nucleoside analog reverse transcriptase inhibitors (NRTIs) in combination with one or two protease inhibitors (PIs) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). These guidelines are based on clinical trials geared toward reducing viral loads to undetectable levels. In 10 to 20 percent of patients, however, such a reduction in viral load will not be accomplished. Virologic failure rates observed in cohort studies in the United States and Europe have reached rates as high as 60 percent after a year of treatment. Some predictors of treatment failure include higher viral load baselines, lower baseline CD4-cell counts, and failure to initiate treatment with an NNRTI. Clearly, better approaches to salvage therapy are needed. Studies include the evaluation of effectiveness of switching treatments from one PI to another, newer drugs, and multidrug regimens. Two tables, involving current guidelines for and major prospective studies on salvage therapy, are provided. In addition, the use of resistance testing in monitoring salvage therapy is discussed.^ieng
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Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Terapia Recuperativa , Quimioterapia Combinada , Humanos , Guías de Práctica Clínica como AsuntoRESUMEN
The advent of triple-drug therapy for HIV disease has raised the concern that disadvantaged patients with multiple social problems may be nonadherent to treatment. Fearing that partial adherence will lead to drug resistance, some clinicians are withholding these powerful new drugs from such patients. The historical record demonstrates that labeling patients as nonadherent may be both stigmatizing and inaccurate. Since 1900, such adjectives as ignorant, vicious, and recalcitrant have been used to describe patients who do not follow medical advice. Less judgmental terms, such as nonadherent and noncompliant, are now used, but these terms still imply that patients should obey physician-imposed regimens. Studies of nonadherence have consistently shown that the problem is widespread among all persons and cannot reliably be predicted on the basis of patient characteristics. This paper argues that physicians should deemphasize the standard approach of predicting and correcting nonadherent behavior in certain patients. Rather, clinicians should encourage all HIV-positive patients to devise individualized treatment plans that can facilitate reliable ingestion of medication. Although the potential development of resistance to triple-drug therapy remains an important public health issue, concern about this possibility must be balanced with respect for patients' rights. Encouraging the active participation of HIV-positive persons in their own treatment will help avoid judgmental and inaccurate assessments of patient behavior and may help patients take medications more successfully.