RESUMEN
BACKGROUND: We hypothesized that drug resistance mutations would impact clinical outcomes associated with HIV-1 infection. METHODS: A matched case-control study of participants in AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT). Cases experienced an AIDS-defining event (ADE) or mortality, and controls did not. One hundred thirty-four cases were identified and matched to a total of 266 controls by age, sex, treatment regimen, and length of follow-up. Both cases and controls had HIV RNA levels of ≥ 500 copies/mL within 24 weeks of an event. Population-based genotyping at or near the time of the event was used to evaluate the impact of resistance mutations on incidence of ADE and/or death using conditional logistic regression models. RESULTS: One hundred four cases and 183 controls were analyzed. Median time to event was 99 weeks; 6 cases were deaths. At baseline, cases had lower CD4 (median 117 vs 235 cells/mm3; P < .0001) and higher HIV RNA levels (median 205,000 vs 57,000 copies/mL; P = .003). No significant differences in resistance were seen between cases and controls. CONCLUSIONS: In this rigorously designed case-control study, lower CD4 cell counts and higher virus loads, not antiretroviral drug resistance, were strongly associated with ADE and mortality.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/mortalidad , Recuento de Linfocito CD4 , Carga Viral , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/inmunología , Síndrome de Inmunodeficiencia Adquirida/virología , Adulto , Estudios de Casos y Controles , Farmacorresistencia Viral , Femenino , Humanos , Modelos Logísticos , Estudios Longitudinales , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios RetrospectivosRESUMEN
BACKGROUND: We devised an open-label, randomized trial to evaluate whether therapeutic drug monitoring (TDM) of protease inhibitors (PIs) and dose escalation based upon a normalized inhibitory quotient (NIQ), which integrates PI trough concentration and drug resistance, could improve virologic outcome in PI-experienced patients with treatment failure. Secondary analyses through 48 weeks are presented. METHODS: Eligible HIV-infected subjects with a screening viral load of ≥ 1000 copies/mL initiated a new PI-based regimen at entry and had NIQ performed at week 2. Subjects with an NIQ ≤1 were randomized at week 4 to a standard-of-care (SOC) arm or TDM arm featuring PI dose escalation. RESULTS: One hundred and eighty-three subjects were randomized. There was no significant treatment difference in change from randomization to week 48 in HIV-1 RNA [ P = .13, median (25th, 75th percentile log10 copies/mL change): -0.03 (-0.74, 0.62) with TDM and 0.11 (-2.3, 0.82) with SOC]. In subgroup analysis, patients with ≥ 0.69 active PIs benefited from TDM compared to those with <0.69 active PIs ( P = .05). CONCLUSIONS: While the TDM strategy of PI dose escalation did not improve virologic response at week 48 overall, in subgroup analysis, TDM favorably impacted virologic outcome in subjects taking PI-based regimens with moderate antiviral activity.
Asunto(s)
Monitoreo de Drogas , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/efectos de los fármacos , Adulto , Recuento de Linfocito CD4 , Femenino , Estudios de Seguimiento , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Carga ViralRESUMEN
In a randomized trial, AIDS Clinical Trials Group (ACTG) protocol 5146 (A5146) investigated the use of therapeutic drug monitoring (TDM) to adjust doses of HIV-1 protease inhibitors (PIs) in patients with prior virologic failure on PI-based therapy who were starting a new PI-based regimen. The overall percentage of "PI trough repeats" such as rescheduled visits or redrawn PI trough specimens increased from 2% to 5% to 10% as the process progressed from the clinical sites, the pharmacology specialty laboratory, and the study team, respectively. Cumulatively, this represents a 17% rate of failure to obtain adequate PI trough sample. While targeting a turnaround of 7 days or less from sample receipt to a drug concentration report, 12% of the received specimens required a longer period to report concentrations. The implementation of dosing changes in the TDM arm were achieved within 7 days or less for 56% of the dose change events and within 14 days or less for 77% of dose change events. This quality assurance analysis provides a valuable summary of the specific points in the TDM process that could be improved during a multicenter clinical trial including: 1) shortening the timeline of sample shipment from clinical site to the laboratory; 2) performing the collection of PI trough specimen within the targeted sampling window by careful monitoring of the last dose times and collection times by the clinicians; 3) increasing patient adherence counseling to reduce the number of samples that are redrawn due to suspecting inconsistent adherence; and 4) decreasing the time to successful TDM-based dose adjustment. The application of some of these findings may also be relevant to single-center studies or clinical TDM programs within a hospital.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Monitoreo de Drogas/normas , Fármacos Anti-VIH/sangre , Calibración , Inhibidores de la Proteasa del VIH/sangre , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1 , Humanos , Laboratorios/normas , Control de Calidad , Manejo de Especímenes/normas , Resultado del TratamientoRESUMEN
The AIDS Clinical Trials Group designed and implemented a prospective, randomized, strategy trial in antiretroviral-experienced, HIV-infected patients to evaluate the virologic impact of protease inhibitor dose escalation in response to therapeutic drug monitoring (TDM) with an inhibitory quotient, which integrates both drug exposure and viral drug resistance. In the process of developing this clinical trial, several unique challenges were identified that required innovative solutions. The major challenge was the need to integrate resistance testing, pharmacokinetic data, medication adherence, toxicity data, clinical assessments, randomization assignment, and protocol-specified clinical management in a way that could be utilized in real time by the protocol team, communicated promptly to the clinical sites, and transmitted accurately to the study database. In addition, the protocol team had to address the relative lack of commercially available TDM laboratories in the United States that were experienced in antiretroviral drug assays and a lack of familiarity with the principles of pharmacokinetic monitoring at participating clinical sites. This article outlines the rationale for the design of this strategy trial, specific barriers to implementation that were identified, and solutions that were developed with the hope that these experiences will facilitate the design and conduct of future trials of TDM.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Monitoreo de Drogas , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , VIH/efectos de los fármacos , VIH/fisiología , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Proyectos de InvestigaciónRESUMEN
OBJECTIVES: Complex antiretroviral regimens can be associated with increased toxicity and poor adherence. Our aim was to compare the efficacy and safety of switching to two simplified, class-sparing antiretroviral regimens. METHODS: We conducted a randomized, open-label study in 236 patients with virologic suppression who were taking a three- or four-drug protease inhibitor or non-nucleoside reverse transcriptase inhibitor regimen for > or = 18 months. Patients received lopinavir/ritonavir (LPV/r) 533 mg/133 mg twice daily + efavirenz (EFV) 600 mg once daily or EFV + two nucleoside reverse transcriptase inhibitors (NRTI). Primary study endpoint was time to first virologic failure (VF, confirmed HIV-1 RNA > 200 copies/ml) or discontinuation because of study drug-related toxicity. RESULTS: After 2.1 years of follow up, patients receiving LPV/r + EFV discontinued treatment at a greater rate than patients receiving EFV + NRTI (P < 0.001). Twenty-one patients developed VF (14 receiving LPV/r + EFV and seven receiving EFV + NRTI) and 26 discontinued because of a study drug-related toxicity (20 receiving LPV/r + EFV and six receiving EFV + NRTI). Time to VF or study drug related-toxicity discontinuation was significantly shorter for LPV/r + EFV than EFV + NRTIs (P = 0.0015). A significantly higher risk of drug-related toxicity occurred with LPV/r + EFV, mainly for increased triglycerides (P = 0021). A trend toward a higher VF rate occurred with LPV/r + EFV in an intent-to-treat and as-treated analyses (P = 0.088 and P = 0.063 respectively). CONCLUSIONS: Switching to EFV + NRTI resulted in better outcomes, fewer drug-related toxicity discontinuations and a trend to fewer virologic failures compared to switching to LPV/r + EFV.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Adulto , Alquinos , Fármacos Anti-VIH/efectos adversos , Terapia Antirretroviral Altamente Activa/métodos , Benzoxazinas/efectos adversos , Benzoxazinas/uso terapéutico , Recuento de Linfocito CD4 , Ciclopropanos , Farmacorresistencia Viral , Femenino , Estudios de Seguimiento , Infecciones por VIH/inmunología , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/efectos de los fármacos , Humanos , Lopinavir , Masculino , Persona de Mediana Edad , Pirimidinonas/efectos adversos , Pirimidinonas/uso terapéutico , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Ritonavir/efectos adversos , Ritonavir/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVE: We evaluated the safety, tolerability and antiretroviral activity of beta-D-2,6-diaminopurine dioxolane (DAPD; amdoxovir) with or without mycophenolate mofetil (MMF) in HIV-1 infection following extensive antiretroviral therapy (ART). METHODS: Oral DAPD 500 mg twice daily with placebo or MMF 500 mg twice daily was added to failing ART. HIV-1 RNA viral load (VL) decline to week 2 was analyzed by intent-to-treat, using rank-based tests. Patients with VL decline > 0.5 log10 copies/ml at week 2 (virologic response, VR) optimized ART and continued therapy for up to 96 weeks. RESULTS: Forty adults with median VL 4.5 log10 copies/ml, median 184 CD4+ cells/microl, and a median of 6 nucleoside reverse transcriptase inhibitor (NRTI) mutations (range, 1-8) were randomized. Median VL reduction at week 2 was -0.26 log10 copies/ml (P < 0.0001). Response to DAPD/placebo (median -0.37 log10 copies/ml) was unexpectedly greater than to DAPD/MMF (median -0.23 log10 copies/ml), although this difference was not statistically significant (P = 0.59). MMF appeared to lower concentrations of DAPD and its metabolite dioxolane guanosine. Of 10 patients with VR (DAPD 7, DAPD/MMF 3), four persisted beyond week 24. VR was more frequent with < or = 5 baseline NRTI mutations (P = 0.12) or < 4 thymidine-associated mutations (TAMs) without E44D or V118I (P = 0.08). Twenty-three patients received extended DAPD +/- MMF; five beyond week 24. Few adverse events were related to study medications. CONCLUSIONS: The addition of DAPD +/- MMF to failing therapy appears safe and well tolerated. DAPD had significant activity at week 2 (mean -0.35 log10) in heavily pretreated patients that was not augmented by MMF.
Asunto(s)
Dioxolanos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Inmunosupresores/uso terapéutico , Ácido Micofenólico/análogos & derivados , Nucleósidos de Purina/uso terapéutico , Adulto , Anciano , Método Doble Ciego , Farmacorresistencia Viral , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , ARN Viral/sangre , Resultado del Tratamiento , Carga ViralRESUMEN
OBJECTIVE: Whether therapeutic drug monitoring of protease inhibitors improves outcomes in HIV-infected patients is controversial. We evaluated this strategy in a randomized, open-label clinical trial, using a normalized inhibitory quotient (NIQ), which incorporates drug exposure and viral drug resistance. NIQs < or = 1 may predict poor outcome and identify patients who could benefit from dose escalation. DESIGN/METHODS: Eligible patients had a viral load > or =1000 copies/ml on a failing regimen, and began a new protease inhibitor containing regimen at entry. All FDA-approved protease inhibitors available during the study recruitment (June 2002-May 2006) were allowed. One hundred and eighty-three participants with NIQ < or = 1, on the basis of their week 2 protease inhibitor trough concentration and pre-entry drug resistance test, were randomized at week 4 to standard of care (SOC) or protease inhibitor dose escalation (TDM). The primary endpoint was change in log10 plasma HIV-1 RNA concentration from randomization to 20 weeks later. RESULTS: Ninety-one patients were randomized to SOC and 92 to TDM. NIQs increased more in the TDM arm compared to SOC (+69 versus +25%, P = 0.01). Despite this, TDM and SOC arms showed no difference in outcome (+0.09 versus +0.02 log10, P = 0.17). In retrospective subgroup analyses, patients with less HIV resistance to their protease inhibitors benefited from TDM (P = 0.002), as did black and Hispanic patients (P = 0.035 and 0.05, respectively). Differences between black and white patients persisted when accounting for protease inhibitor susceptibility. CONCLUSIONS: There was no overall benefit of TDM. In post hoc subgroup analyses, TDM appeared beneficial in black and Hispanic patients, and in patients whose virus retained some susceptibility to the protease inhibitors in their regimen.
Asunto(s)
Monitoreo de Drogas/métodos , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/efectos de los fármacos , Adulto , Terapia Antirretroviral Altamente Activa , Esquema de Medicación , Farmacorresistencia Viral , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/sangre , VIH-1/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Resultado del Tratamiento , Carga ViralRESUMEN
BACKGROUND: Adherence to antiretroviral therapy is difficult, and methods to increase it are needed. METHODS: We tested the impact of supportive telephone calls in an adherence substudy of a treatment trial. Subjects initiating antiretroviral therapy received either each site's usual adherence support measures or usual support measures and scripted serial telephone calls (16 calls during 96 weeks). RESULTS: A total of 282 subjects enrolled: 140 in the usual support measures group and 142 in the calls group. A total of 75% of expected calls were completed. Virologic failure occurred in 97 (34%) subjects: 52 (37%) of those in the usual support measures group and 45 (32%) of those in the calls group; time to virologic failure was not different (P=.32). In each group, >72% of subjects reported > or =95% adherence, with no difference between groups. Independent predictors of higher rates of virologic failure were <95% adherence, receiving the 4-drug regimen with nelfinavir, and female sex; older age was associated with decreased likelihood of virologic failure. Receiving the 4-drug regimen with nelfinavir, higher stress scores, older age, and higher call completion rates were independently associated with higher adherence. CONCLUSIONS: Serial telephone calls did not improve virologic outcome but had an impact on self-reported adherence.