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1.
J Antimicrob Chemother ; 75(5): 1301-1310, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31976521

RESUMO

OBJECTIVES: To evaluate the prevalence and therapeutic relevance of drug resistance among isolates from ART-experienced HIV-1-infected patients over the past two decades in Italy. METHODS: Dynamics of resistance to one, two and three or more antiretroviral classes were evaluated from 1999-2018. Virological success (VS) after the latest therapy switch was evaluated according to cumulative class resistance and cumulative genotypic susceptibility score (Stanford HIV_DB algorithm). RESULTS: Among 13 663 isolates (from 6739 patients), resistance to at least one drug class decreased sharply from 1999 to 2010 (≤2001, 84.6%; 2010, 43.6%; P < 0.001), then remained relatively constant at ∼40% during 2010-18, with the proportion of resistance to three or more classes also stable (∼5%). After 2008, integrase inhibitor resistance slightly increased from 5.6% to 9.7% in 2018 and contributed to resistance, particularly in isolates with resistance to three or more classes (one class, 8.4%; two classes, 15.3%; three or more classes, 34.7%, P < 0.001). Among 1827 failing patients with an available follow-up, by 1 year after genotype-guided therapy start the probability of VS was 87.6%. Patients with cumulative resistance to three or more classes and receiving a poorly active regimen showed the lowest probability (62.6%) of VS (P < 0.001) compared with all other patients (≥81.8%). By Cox regression analysis, cumulative MDR and receiving poorly active antiretroviral regimens were associated with a lower hazard of VS compared with those without resistance. CONCLUSIONS: A dramatic drop of HIV-1 drug resistance at failure has been achieved over the last two decades in Italy; resistance to three or more classes is low but present among currently failing patients. Its management still requires a rational and careful diagnostic and therapeutic approach.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Farmacorresistência Viral/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , HIV-1/genética , Humanos , Itália/epidemiologia , Falha de Tratamento
2.
J Antimicrob Chemother ; 73(9): 2485-2492, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29873733

RESUMO

Background: Integrase strand transfer inhibitors (INSTIs) are recommended by international guidelines as first-line therapy in antiretroviral-naive and -experienced HIV-1-infected patients. Objectives: This study aimed at evaluating the prevalence at failure of INSTI-resistant variants and the impact of baseline minority resistant variants (MiRVs) on the virological response to an INSTI-based regimen. Methods: Samples at failure of 134 patients failing a raltegravir-containing (n = 65), an elvitegravir-containing (n = 20) or a dolutegravir-containing (n = 49) regimen were sequenced by Sanger sequencing and ultra-deep sequencing (UDS). Baseline samples of patients with virological failure (VF) (n = 34) and of those with virological success (VS) (n = 31) under INSTI treatment were sequenced by UDS. Data were analysed using the SmartGene platform, and resistance was interpreted according to the ANRS algorithm version 27. Results: At failure, the prevalence of at least one INSTI-resistant variant was 39.6% by Sanger sequencing and 57.5% by UDS, changing the interpretation of resistance in 17/134 (13%) patients. Among 53 patients harbouring at least one resistance mutation detected by both techniques, the most dominant INSTI resistance mutations were N155H (45%), Q148H/K/R (23%), T97A (19%) and Y143C (11%). There was no difference in prevalence of baseline MiRVs between patients with VF and those with VS. MiRVs found at baseline in patients with VF were not detected at failure either in majority or minority mutations. Conclusions: UDS is more sensitive than Sanger sequencing at detecting INSTI MiRVs at treatment failure. The presence of MiRVs at failure could be important to the decision to switch to other INSTIs. However, there was no association between the presence of baseline MiRVs and the response to INSTI-based therapies in our study.


Assuntos
Terapia Antirretroviral de Alta Atividade/métodos , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Adulto , Feminino , Técnicas de Genotipagem , Infecções por HIV/epidemiologia , HIV-1/genética , HIV-1/isolamento & purificação , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Paris/epidemiologia , Prevalência , Falha de Tratamento
3.
J Antimicrob Chemother ; 73(8): 2147-2151, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29718247

RESUMO

Background: Atazanavir is a PI widely used as a third agent in combination ART. We aimed to determine the prevalence and the patterns of resistance in PI-naive patients failing on an atazanavir-based regimen. Methods: We analysed patients failing on an atazanavir-containing regimen used as a first line of PI therapy. We compared the sequences of reverse transcriptase and protease before the introduction of atazanavir and at failure [two consecutive viral loads (VLs) >50 copies/mL]. Resistance was defined according to the 2014 Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) algorithm. Results: Among the 113 patients, atazanavir was used in the first regimen in 71 (62.8%) patients and in the first line of a PI-based regimen in 42 (37.2%). Atazanavir was boosted with ritonavir in 95 (84.1%) patients and combined with tenofovir/emtricitabine or lamivudine (n = 81) and abacavir/lamivudine or emtricitabine (n = 22). At failure, median VL was 3.05 log10 copies/mL and the median CD4+ T cell count was 436 cells/mm3. The median time on atazanavir was 21.2 months. At failure, viruses were considered resistant to atazanavir in four patients (3.5%) with the selection of the following major atazanavir-associated mutations: I50L (n = 1), I84V (n = 2) and N88S (n = 1). Other emergent PI mutations were L10V, G16E, K20I/R, L33F, M36I/L, M46I/L, G48V, F53L, I54L, D60E, I62V, A71T/V, V82I/T, L90M and I93L/M. Emergent NRTI substitutions were detected in 21 patients: M41L (n = 2), D67N (n = 3), K70R (n = 1), L74I/V (n = 3), M184V/I (n = 16), L210W (n = 1), T215Y/F (n = 3) and K219Q/E (n = 2). Conclusions: Resistance to atazanavir is rare in patients failing the first line of an atazanavir-based regimen according to the ANRS. Emergent NRTI resistance-associated mutations were reported in 18% of patients.


Assuntos
Sulfato de Atazanavir/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1/genética , Adulto , Didesoxinucleosídeos , Combinação de Medicamentos , Emtricitabina/uso terapêutico , HIV-1/efeitos dos fármacos , Humanos , Lamivudina , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Tenofovir/uso terapêutico , Falha de Tratamento , Carga Viral
4.
HIV Med ; 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30004176

RESUMO

OBJECTIVES: To compare nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-sparing regimens with tenofovir alafenamide (TAF)-based combinations in HIV-1-infected adults, we performed a network meta-analysis (NMA) to provide estimates of relative efficacy for these two regimens. METHODS: A systematic literature review (SLR) was performed to identify phase 3/4 randomized controlled clinical trials evaluating the efficacy of commonly used combination antiretroviral therapy (cART) including an NRTI backbone or that of commonly used NRTI-sparing regimens. A Bayesian random-effect model was used to compare virological suppression rates at 48 weeks for NRTI-sparing regimens and elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF). RESULTS: Twenty-three studies in treatment-naïve patients identified by the SLR were included in the NMA, including four studies assessing NRTI-sparing regimens. In treatment-naïve patients, the probability of achieving virological suppression at 48 weeks was between 40% and 60% higher with E/C/F/TAF than with NRTI-sparing strategies. The credible interval vs. darunavir/ritonavir (DVR/r) + raltegravir (RAL) and LPV/r monotherapy did not include 1. In the subgroup of naïve patients with viral load < 100 000 HIV-1 RNA copies/mL, a credible difference was found between NRTI-sparing treatments and E/C/F/TAF. Studies in treatment-experienced patients were too heterogeneous to allow for an NMA. CONCLUSIONS: The NMA results suggest that E/C/F/TAF represents a more effective option than NRTI-sparing regimens in terms of 48-week efficacy in treatment-naïve patients. Furthermore, TAF pharmacological properties, as well as tolerability results in clinical studies, suggest a safety profile similar to that of NRTI-sparing regimens. Thus, the E/C/F/TAF combination might represent a more appropriate option than NRTI-sparing regimens for initiation of antiretroviral therapy in treatment-naïve HIV-infected patients.

5.
J Antimicrob Chemother ; 71(8): 2248-51, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27231280

RESUMO

OBJECTIVES: In the context of a rilpivirine/emtricitabine/tenofovir disoproxil fumarate switch in HIV-1-infected patients with at least 1 year of virological success, we determined whether proviral DNA is an alternative to plasma HIV RNA for resistance genotyping. METHODS: Resistance-associated mutations (RAMs) in DNA after at least 1 year of virological success [viral load (VL) <50 copies/mL] were compared with those identified in the last plasma RNA genotype available. Rilpivirine/emtricitabine/tenofovir disoproxil fumarate RAMs studied were K65R, L100I, K101E/P, E138A/G/K/R/Q, V179L, Y181C/I/V, M184V/I, Y188L, H221Y, F227C and M230I/L in the RT. We studied patients without virological failure (VF) and with at least 1 VF (two consecutive VLs >50 copies/mL). Kappa's coefficient was used to measure agreement between the DNA and RNA genotypes. RESULTS: In patients without VF (n = 130) and with VF (n = 114), RNA and DNA showed resistance to at least one drug of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination in 8% and 9% and in 60% and 45%, respectively. For rilpivirine RAMs, correlation between RNA and DNA was higher in patients without VF than in patients with VF (kappa = 0.60 versus 0.19, P = 0.026). Overall, the prevalence of RAMs was lower in DNA than in RNA. CONCLUSIONS: Incomplete information provided by the DNA genotypic test is more notable in patients with VF, suggesting that all resistance mutations associated with prior VF have not been archived in the proviral DNA or decreased to a level below the threshold of detection. In the case where no historical plasma genotypic test is available, DNA testing might be useful to rule out switching to rilpivirine/emtricitabine/tenofovir disoproxil fumarate.


Assuntos
Fármacos Anti-HIV/uso terapêutico , DNA Viral/genética , Farmacorresistência Viral , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Rilpivirina/uso terapêutico , Tenofovir/uso terapêutico , Genótipo , Técnicas de Genotipagem/métodos , Infecções por HIV/virologia , Humanos , Testes de Sensibilidade Microbiana/métodos , Mutação , Provírus/genética , RNA Viral/genética
6.
HIV Med ; 17(5): 380-4, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27093565

RESUMO

OBJECTIVES: To compare the efficacy, in current clinical practice, of first regimens containing abacavir with lamivudine (ABC/3TC) or tenofovir with emtricitabine (TDF/FTC) in patients with baseline viral load ≥100,000 HIV-1 RNA copies/mL. METHODS: Using a prospective cohort, we selected all patients starting a first HIV regimen based either on ABC/3TC or on TDF/FTC. The propensity score (PS) method was used to limit the indication bias due to the observational nature of the data. Adjusting and weighting methods via PS were used to compare the effectiveness of a first regimen containing ABC/3TC or TDF/FTC. The primary outcome was treatment failure by month 12 (M12). RESULTS: Overall, 2781 patients started an antiretroviral (ARV) regimen with ABC/3TC or TDF/FTC each in combination with efavirenz, boosted atazanavir or boosted darunavir. Among the 2472 uncensored patients before M12, 962 (39%) had a baseline viral load ≥100,000 copies/mL of whom 294 were in treatment failure at or before M12. Our analyses showed no difference between ABC/3TC and TDF/FTC in the risk of treatment failure at M12 in patients starting an ARV regimen with a high viral load (≥100,000 copies/mL). CONCLUSIONS: Using a large prospectively collected cohort of patients seeking care in France, we found no evidence that ABC/3TC based regimens led to more failures than TDF/FTC based ones in patients with high baseline viral loads.


Assuntos
Didesoxinucleosídeos/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Lamivudina/uso terapêutico , Tenofovir/uso terapêutico , Carga Viral/efeitos dos fármacos , Didesoxinucleosídeos/farmacologia , Quimioterapia Combinada , Emtricitabina/farmacologia , Feminino , França , Humanos , Lamivudina/farmacologia , Masculino , Pontuação de Propensão , Estudos Prospectivos , Medição de Risco , Falha de Tratamento
7.
HIV Med ; 16(5): 297-306, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25585664

RESUMO

OBJECTIVES: This observational study in antiretroviral treatment-experienced, HIV-1-infected adults explored the efficacy of etravirine plus darunavir/ritonavir (DRV group; n = 999) vs. etravirine plus an alternative boosted protease inhibitor (other PI group; n = 116) using pooled European cohort data. METHODS: Two international (EuroSIDA; EUResist Network) and five national (France, Italy, Spain, Switzerland and UK) cohorts provided data (collected in 2007-2012). Stratum-adjusted (for confounding factors) Mantel-Haenszel differences in virological responses (viral load < 50 HIV-1 RNA copies/mL) and odds ratios (ORs) with 95% confidence intervals (CIs) were derived. RESULTS: Baseline characteristics were balanced between groups except for previous use of antiretrovirals (≥ 10: 63% in the DRV group vs. 49% in the other PI group), including previous use of at least three PIs (64% vs. 53%, respectively) and mean number of PI resistance mutations (2.3 vs. 1.9, respectively). Week 24 responses were 73% vs. 75% (observed) and 49% vs. 43% (missing = failure), respectively. Week 48 responses were 75% vs. 73% and 32% vs. 30%, respectively. All 95% CIs around unadjusted and adjusted differences encompassed 0 (difference in responses) or 1 (ORs). While ORs by cohort indicated heterogeneity in response, for pooled data the difference between unadjusted and adjusted for cohort ORs was small. CONCLUSIONS: These data do not indicate a difference in response between the DRV and other PI groups, although caution should be applied given the small size of the other PI group and the lack of randomization. This suggests that the efficacy and virology results from DUET can be extrapolated to a regimen of etravirine with a boosted PI other than darunavir/ritonavir.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , Piridazinas/administração & dosagem , Ritonavir/administração & dosagem , Sulfonamidas/administração & dosagem , Contagem de Linfócito CD4 , Darunavir , Quimioterapia Combinada , Feminino , França/epidemiologia , Infecções por HIV/epidemiologia , Humanos , Itália/epidemiologia , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Nitrilas , Razão de Chances , Pirimidinas , Espanha/epidemiologia , Suíça/epidemiologia , Reino Unido/epidemiologia , Carga Viral
8.
J Antimicrob Chemother ; 69(4): 1086-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24302653

RESUMO

OBJECTIVES: In the context of simplification strategies, it is essential to know the feasibility of a switch to a rilpivirine-based therapy. The aim of this study was to describe rilpivirine, tenofovir and emtricitabine resistance in HIV-1-infected patients who experienced virological failure during their previous antiretroviral treatment. PATIENTS AND METHODS: The studied population included two groups of patients, all rilpivirine naive, tested for resistance by bulk sequencing from 2008 to 2011: the first group (n = 998) failing a nucleoside reverse transcriptase inhibitor (NRTI) plus boosted protease inhibitor (PI)-based regimen and the second group (n = 3733) failing an NRTI plus non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. RESULTS: In the first group, the frequency of rilpivirine mutations and resistance to rilpivirine (5.1%) was similar to that in antiretroviral-naive HIV-1-infected patients. Among the 1605 patients from the second group with at least one NNRTI mutation in their HIV, the prevalence of viruses 'resistant' or 'possibly resistant' to efavirenz, nevirapine and etravirine was 78%, 79% and 74%, respectively, while 59% were resistant to rilpivirine. Resistance to rilpivirine was significantly more frequent in non-B subtype versus B subtype viruses. Among pretreated patients with viruses with at least one NNRTI mutation (other than for rilpivirine), 22% of sequences were susceptible to the combination rilpivirine/emtricitabine/tenofovir disoproxil fumarate. CONCLUSIONS: In patients failing an NRTI plus NNRTI-based regimen, to know the feasibility of a switch to rilpivirine/emtricitabine/tenofovir disoproxil fumarate, reliable resistance information should be available at the time of use of concurrent NNRTI therapy.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/farmacologia , Desoxicitidina/análogos & derivados , Farmacorresistência Viral , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Nitrilas/farmacologia , Organofosfonatos/farmacologia , Pirimidinas/farmacologia , Adenina/farmacologia , Desoxicitidina/farmacologia , Emtricitabina , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Humanos , Rilpivirina , Análise de Sequência de DNA , Tenofovir , Falha de Tratamento
9.
J Antimicrob Chemother ; 68(6): 1237-42, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23361642

RESUMO

OBJECTIVES: The prevalence of rilpivirine, emtricitabine and tenofovir resistance-associated mutations (RAMs), described in vitro and in vivo, was determined in antiretroviral-naive patients. PATIENTS AND METHODS: From 2008 to 2011, 1729 treatment-naive patients were tested for resistance by bulk sequencing. We studied the primary rilpivirine RAMs (K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, H221Y, F227C and M230I/L) and other potential rilpivirine-associated mutations (V90I, L100I, K101T, E138S, V179D/I, Y188L, V189I, G190A/E/S and M230V). We also studied the M184V/I and K65R mutations for emtricitabine and tenofovir, respectively. RESULTS: Among 1729 sequences, half of patients had B-subtype viruses and the other half non-B (with 26.7% CRF02, n=461). Primary rilpivirine RAMs were infrequent (4.6%, n=79) and the most prevalent were E138A (3%, n=52), E138K, (0.3%, n=5), H221Y (0.3%, n=5), E138G (0.2%, n=4) and Y181C (0.2%, n=4). The frequency of the primary rilpivirine RAMs was similar between B and non-B subtypes. The other potential rilpivirine-associated mutations that were most prevalent were V179I (8.4%, n=145), V90I (3.8%, n=65) and V189I (2.3%, n=40). The common V179I, V189I and V90I polymorphisms have not been associated with virological failure in Phase 3 clinical studies. By the ANRS algorithm, 4.9% (n=84) of samples were resistant to rilpivirine, 3.7% (n=32) of B-subtype viruses versus 6% (n=52) of non-B-subtype viruses (P=0.02, χ(2) test). The prevalence of K65R and M184I/V was 0.06% (1/1729) and 1% (18/1729), respectively. The prevalence of K103N was 2% (35/1729). CONCLUSIONS: The prevalence of rilpivirine, emtricitabine and tenofovir resistance mutations was very low in antiretroviral-naive patients. The prevalence of resistance to rilpivirine (4.9%, n=84) was not statistically different from the prevalence of efavirenz and nevirapine resistance in our population.


Assuntos
Adenina/análogos & derivados , Desoxicitidina/análogos & derivados , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Mutação/genética , Mutação/fisiologia , Nitrilas/farmacologia , Organofosfonatos/farmacologia , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Adenina/farmacologia , Terapia Antirretroviral de Alta Atividade , Desoxicitidina/farmacologia , Emtricitabina , Genótipo , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Prevalência , Rilpivirina , Tenofovir
10.
J Antimicrob Chemother ; 67(3): 691-5, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22160145

RESUMO

OBJECTIVES: Long-term results at week 96 are needed to evaluate the capacity of the darunavir/ritonavir monotherapy strategy to maintain a sustained control of the HIV-1 viral load. METHODS: MONOI is a prospective, open-label, non-inferiority, randomized, 96 week trial comparing darunavir/ritonavir monotherapy versus a darunavir/ritonavir triple-therapy strategy to maintain HIV-1 viral load suppression in HIV-1-infected patients. CLINICAL TRIAL REGISTRATION: NCT00412551. RESULTS: From 225 randomized patients, 219 patients reached the 48 week follow-up and 211 reached the 96 week follow-up (106 patients in the darunavir monotherapy arm and 105 in the darunavir triple-therapy arm). Baseline characteristics were well balanced between the two treatment groups. At week 96, in intent-to-treat analysis, 91/103 patients (88%, 95% CI 81-94) allocated to the darunavir/ritonavir monotherapy arm and 87/104 patients (84%, 95% CI 75-90) allocated to the darunavir triple-therapy arm achieved an HIV-1 viral load <50 copies/mL, with no statistical difference between the two groups. Throughout the 96 week follow-up, 66/112 patients (59%, 95% CI 49-68) and 79/113 patients (70%, 95% CI 61-78) consistently had HIV-1 RNA <50 copies/mL with darunavir/ritonavir monotherapy and darunavir/ritonavir triple therapy, respectively. CONCLUSIONS: The MONOI study establishes darunavir/ritonavir monotherapy as durable and efficacious for maintaining virological suppression in HIV-1 patients. Darunavir/ritonavir monotherapy should be considered as a (tailored) treatment option for standard triple-therapy patients who have had a substantial period of viral suppression.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Ritonavir/administração & dosagem , Sulfonamidas/administração & dosagem , Carga Viral , Darunavir , Humanos , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
11.
HIV Med ; 13(8): 505-15, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22416798

RESUMO

OBJECTIVES: The aim of the study was to evaluate fat tissue distribution in HIV-infected patients with suppressed viraemia treated with darunavir/ritonavir (darunavir/r) monotherapy versus darunavir/r triple therapy. METHODS: This study was a substudy of the randomized, multicentre, open-label MONOI-ANRS 136 trial. Body fat distribution and metabolic parameters were measured at baseline, week 48 and week 96. RESULTS: In total, 156 patients of the 225 initially enrolled in the MONOI trial participated in this study, 75 in the darunavir/r monotherapy arm and 81 in the darunavir/r triple-therapy arm. The median limb fat increase from baseline was +0.34 kg [interquartile range (IQR) -0.040 to +1.140 kg; P < 0.001] at week 48 and +0.33 kg (IQR -0.14 to +1.26 kg; P = 0.001) at week 96 in the monotherapy arm, while there was no change (-0.02 kg; IQR -0.53 to +0.52 kg) at week 48 and then an increase of +0.23 kg (IQR -0.45 to +0.87 kg; P = 0.046) at week 96 in the triple-therapy arm. The two arms differed significantly at week 48 (P = 0.001) but not at week 96. The median increase in trunk fat was +0.73 kg (IQR -0.24 to +1.60 kg; P < 0.001) and 0.60 kg (IQR -0.41 to +1.49 kg; P = 0.03) at week 48 and +1.16 kg (IQR -0.17 to +2.75 kg; P < 0.001) and +0.90 kg (IQR -0.51 to +2.34 kg; P = 0.001) at week 96 in the monotherapy and triple-therapy arms, respectively, with no difference between arms. At week 96, the only biological change was a glucose level elevation in the monotherapy arm (median +4.0 mg/dL; IQR -4.0 to +7.0 mg/dL) compared with the triple-therapy arm (P = 0.012). CONCLUSIONS: Overall, body fat tissue increased in patients on darunavir/r monotherapy and triple therapy, with no difference between the arms over 96 weeks. The only difference found was a delayed increase in limb fat tissue in the triple-therapy arm compared with the monotherapy arm in the first year.


Assuntos
Distribuição da Gordura Corporal , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Síndrome de Lipodistrofia Associada ao HIV/induzido quimicamente , Inibidores da Transcriptase Reversa/administração & dosagem , Ritonavir/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Darunavir , Quimioterapia Combinada/métodos , Feminino , França , Infecções por HIV/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/efeitos adversos , Ritonavir/efeitos adversos , Sulfonamidas/efeitos adversos
12.
Infect Dis Now ; 51(1): 90-93, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33007401

RESUMO

BACKGROUND: Tuberculosis is associated with a risk of immune reconstitution inflammatory syndrome (IRIS) after ART initiation. METHODS: Data from all patients with newly diagnosed tuberculosis disease and uncontrolled HIV infection from 1997 to 2017 in a French center were retrospectively collected. We evaluated the incidence of tuberculosis-IRIS in patients initiating ART with or without integrase inhibitors (INSTI) RESULTS: Fifty-five patients were included: 21 receiving an INSTI regimen and 34 a non-INSTI regimen. Except with regard to ART regimen, the two groups were comparable (median CD4 of 85/mm3). The overall percentage of IRIS was 34% (19/55), with 52% IRIS in INSTI regimen and 23% in non-INSTI regimen respectively (P=0.04). In a multivariate logistic model, we observed an increased risk of IRIS in the INSTI regimen compared to the non-INSTI, with an OR at 3.33 [95% CI, 1.01-11.1] (P=0.05) CONCLUSIONS: ART containing integrase inhibitors could be associated with increased incidence of TB-associated IRIS.


Assuntos
Infecções por HIV/tratamento farmacológico , Síndrome Inflamatória da Reconstituição Imune/epidemiologia , Inibidores de Integrase/efeitos adversos , Tuberculose/epidemiologia , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Feminino , Infecções por HIV/epidemiologia , Humanos , Incidência , Inibidores de Integrase/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Adulto Jovem
13.
HIV Med ; 11(2): 137-42, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19682100

RESUMO

BACKGROUND: The toxicities, cost and complexity of triple combinations warrant the search for other treatment options, such as boosted protease inhibitor (PI) monotherapy. MONotherapy AntiRetroviral Kaletra (MONARK) is the first randomized trial comparing lopinavir/ritonavir monotherapy to triple combination therapy with zidovudine/lamivudine and lopinavir/ritonavir in antiretroviral-naïve patients. METHODS: A total of 136 antiretroviral-naïve patients, with a CD4 cell count above 100 cells/microL and a plasma HIV RNA below 100,000 HIV-1 RNA copies/mL, were randomized and dosed with either lopinavir/ritonavir monotherapy (n = 83) or lopinavir/ritonavir + zidovudine/lamivudine (n = 53). We focus here on patients in the lopinavir/ritonavir monotherapy arm followed to week 96. The intent-to-treat (ITT) analysis initially involved all patients randomized to lopinavir/ritonavir monotherapy (n = 83), and then focused on patients who had an HIV RNA < 50 copies/mL at week 48 (n = 56). RESULTS: At week 96, 39 of 83 patients (47%) had HIV RNA < 50 copies/mL, five of 83 had HIV RNA between 50 and 400 copies/mL, and three of 83 had HIV RNA > 400 copies/mL. Focusing on the 56 patients with an HIV RNA < 50 copies/mL at week 48, 38 of 56 patients (68%) had a sustained HIV RNA < 50 copies/mL to week 96. To week 96, a total of 28 patients (34%) had discontinued the study treatment. In addition, the allocated treatment was changed for seven patients. PI-associated resistance mutations were evident in five of 83 patients in the monotherapy arm from baseline to week 96. CONCLUSION: By ITT analysis, 39 of the 83 patients initially randomized to lopinavir/ritonavir monotherapy had HIV RNA < 50 copies/mL at week 96. The occurrence in some patients of low-level viraemia (50-500 copies/mL) may increase the risk of drug resistance. First-line lopinavir/ritonavir monotherapy cannot be systematically recommended.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1 , Pirimidinonas/uso terapêutico , Ritonavir/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Esquema de Medicação , Farmacorresistência Viral/genética , Quimioterapia Combinada , Seguimentos , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Análise de Intenção de Tratamento , Lamivudina/uso terapêutico , Lopinavir , Masculino , Adesão à Medicação , RNA Viral/sangue , RNA Viral/genética , Inibidores da Transcriptase Reversa/uso terapêutico , Resultado do Tratamento , Zidovudina/uso terapêutico
14.
Encephale ; 35(1): 25-31, 2009 Feb.
Artigo em Francês | MEDLINE | ID: mdl-19250990

RESUMO

INTRODUCTION: The necessary evidence of new therapies of clinical interest extends beyond clinical trials in a less controlled population and closer to clinical practice justified since several years the need of conducting observational, noninterventional studies. Observational studies must include epidemiological (quantitative observational) data to define prevalence and natural history of the target conditions. Moreover, pharmacological interventions in "naturalistic" patients populations, selected by clinicians as per clinical judgment within the scope of the target disease will allow to generate data to complement clinical trials. Clinical trials designed to show robust data on efficacy and tolerability particularly during registration trials must be complemented by robust observational research to confirm and better describe clinical effectiveness in the target population. A noninterventional, observational trial is a study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorization. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnosis or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data. Olanzapine is a new antipsychotic therapy registered in Europe for the treatment of schizophrenia since 1996. AIMS OF THE STUDY: The primary objective of this observational research was to study the evolution of the olanzapine dosage under naturalistic settings. Secondary objectives included patients characteristics, severity of disease, therapeutic evolution and coprescriptions, in a patient's cohort, suffering from schizophrenia, adult patients, diagnosis based on ICD-10; patients were followed during a total of 12 months. DESIGN OF THE STUDY: The cohort study was conducted in France. Between the period of June 2000 and February 2001, 407 psychiatrics randomized to participate in the study had consolidated the patient's cohort. RESULTS: A total of 1810 patients were included, 1093 (60, 4%) male, 717 (39, 6%) females. Age was recorded for a total of 1802 (99, 6%) patients, mean age was 37.8 years as per inclusion criteria and patients consent according to current regulations. Patients entered in the cohort as per clinicians decision underwent a treatment with olanzapine during an outpatient's consultation or at hospitalization. More than two thirds of the patients were followed up during 12 months after onset of this treatment. Clinical outcome was assessed at three, six, nine and 12 months following cohort inclusion using the following tools: CGI, PANSS, Calgary and GAF; as per CGI 78% of the patients cohort were severely ill, the mean PANSS score was 94.1. At second month of treatment clinicians were requested to very well document any changes in olanzapine dosage as well as reasons for the dosage modifications and potential coprescriptions. DISCUSSION: The daily mean dosage of olanzapine was 9.5mg at initiation of treatment, 10.5mg after one month and 11.2mg after 12 months of follow-up. The increase of the dosage after one month was associated with factors such as younger age, schizophrenia diagnosis and severity of the symptoms as measured by CGI and PANSS scores evolution, low initial dosage and hospitalization at treatment initiation. Within the 1810 participants included in the cohort, 1383 (76.5%) received a coprescrition of a psychotropic, for example, 811 (44.8%) a benzodiazepine, 506 (28.0%) an antidepressant. Among the patients cohort that were followed during 12 months, all the clinical and patient-functioning indicators progressed in the direction of a significant improvement.


Assuntos
Antipsicóticos/administração & dosagem , Benzodiazepinas/administração & dosagem , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Adulto , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , França , Humanos , Masculino , Pessoa de Meia-Idade , Olanzapina , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/diagnóstico , Esquizofrenia/diagnóstico , Adulto Jovem
15.
HIV Clin Trials ; 9(3): 147-51, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18547901

RESUMO

OBJECTIVE: To assess virological efficacy of a ritonavir-boosted atazanavir (ATV/r)-containing regimen in patients with persistent viral replication despite HAART. PATIENTS AND METHOD: Prospective cohort of French HIV-infected patients. Patients were included if pretreated and viral load (VL) >400 copies/mL at the time of ATV/r first prescription (baseline). Demographic and epidemiologic data, therapeutic history, and clinical and biological values at baseline and during follow-up were analyzed. Primary endpoint was failure of the regimen defined as either VL>400 copies/mL at Week 24 or treatment interruption before Week 24. Multivariate analysis was performed of baseline characteristics related with treatment failure. RESULTS: There were 424 patients with available data. Primary endpoint was met by 36%: 24% VL>400 copies/mL and 12% treatment interruption. Treatment interruption due to drug-related toxicity was significantly more frequent in women (20.5% vs. 8.8%, p= .001). Female gender (adjusted odds ratio [OR]=1.91), previous use of lopinavir (LPV; OR=2.76), number of new drugs and of active drugs in the regimen (OR=0.48 and 0.3, respectively), and baseline VL (OR=1.75) were independently related with treatment failure. CONCLUSION: ATV/r-containing regimens, because of low pill burden and good tolerance, can be a useful strategy as long as the patients did not suffer previous LPV failures. The issue of gender deserves further studies in larger populations.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Oligopeptídeos/administração & dosagem , Oligopeptídeos/uso terapêutico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Adulto , Sulfato de Atazanavir , Estudos de Coortes , Esquema de Medicação , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , Falha de Tratamento , Replicação Viral/efeitos dos fármacos
16.
HIV Clin Trials ; 6(6): 291-301, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16452063

RESUMO

BACKGROUND: To assess the efficacy and safety of the triple NRTI combination of abacavir (ABC), lamivudine (3TC), and tenofovir (TDF) in a once-daily regimen. METHOD: 38 HIV-naive patients (pts) were treated in a prospective open-arm study over 48 weeks (W48). Virological failure was defined as never achieving plasma HIV-1 RNA < 400 copies/mL or rebound of > or = 0.7 log10. RESULTS: 12/36 (33%) pts had virologic failure at W24 and 10 additional pts had HIV RNA > 50 copies/mL at W12 or W24. There was a significant association between baseline viral load (VL) and virologic failure in 0%, 29%, and 64% pts with baseline VL levels < 4, 4-5, and > 5 log10 copies/mL, respectively (p = .014). 76% of pts developed K65R and M184V/I mutations by W24, and 19% developed M184V/I alone. At W4, 86% of pts had adequate plasma Cmin for the 3 drugs. 14 pts with K65R and M184V/I were given a rescue therapy with a successful outcome (< 50 copies/mL; median follow-up 48 weeks). CONCLUSION: Convergent genetic pathway to resistance, in conjunction with lower antiretroviral potency, may explain the high rate of selection K65R and M184V mutations. These mutations did not appear to have a negative effect on rescue therapy with a variety of regimens.


Assuntos
Didesoxinucleosídeos/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Lamivudina/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4 , Didesoxinucleosídeos/sangue , Feminino , Genótipo , Infecções por HIV/sangue , Infecções por HIV/virologia , Humanos , Lamivudina/sangue , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Projetos Piloto , Estudos Prospectivos , RNA Viral/sangue , Inibidores da Transcriptase Reversa/sangue
17.
J Clin Epidemiol ; 49(8): 899-905, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8699211

RESUMO

Prospective studies have as their goal the estimation of the survival function when the time to the specified event may be censored due to loss to follow-up or to the termination of the study before the event of interest occurs. In such a study, information about an auxiliary event, correlated to the event of interest, is often available. An example of such an auxiliary event in cancer studies is remission or relapse. A stochastic model was proposed by Lagakos, which utilizes this type of information in the analysis of survival studies [1]. The primary objective of using an auxiliary information is to improve the estimation of survival. This article proposes a method to estimate the variance of the estimator of the survival function S(t) for the model including such auxiliary information. Thus, we compute for different situations the relative efficiency of the estimator of S(t) using the stochastic model to the estimator of S(t) using only survival data. The method is applied to data from a prospective study of 379 HIV-seropositive homosexual men, of whom 31 developed AIDS. In our example, the auxiliary event is defined by the level of CD4 lymphocyte counts using distinct threshold values, for instance 200 cells/mm3, while the event of interest is the time to development of AIDS.


Assuntos
Síndrome da Imunodeficiência Adquirida/mortalidade , Modelos Estatísticos , Síndrome da Imunodeficiência Adquirida/imunologia , Contagem de Linfócito CD4 , Intervalos de Confiança , Infecções por HIV/imunologia , Humanos , Masculino , Processos Estocásticos , Análise de Sobrevida
18.
Int J Epidemiol ; 21(2): 222-8, 1992 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-1428473

RESUMO

It is often assumed, but has not been consistently observed, that some characteristics of reproductive history are specifically related to breast cancer of pre- or postmenopausal onset. To determine whether inconsistent reports may be due to differences in definition of menopause, we computed the relative odds (RO) of breast cancer for nulliparity, age at first live birth, family history of breast cancer and prior history of benign breast disease, separately in pre- and postmenopausal women, using seven different definitions of menopause. Results show that (i) relative odds of breast cancer and their confidence intervals may vary according to definitions of menopause; (ii) age-based definitions of menopause are associated with moderate differential misclassification bias between cases and controls; (iii) nulliparity, late age at first birth and family history of breast cancer seem to be specific risk factors for pre- but not postmenopausal breast cancer when cutoff for menopausal status is 10 years or more after last menses; and (iv) when information on menstrual history is not available, 50 years of age may be the best proxy for all menses-based definitions of menopause. We conclude that inconsistent findings on the effect of menopausal status in the association of breast cancer with some reproductive factors are partly due to statistical imprecision and differential misclassification bias associated with different age-based or menses-based definitions of menopause. Researchers should either test whether their conclusions hold using several definitions of menopause or give a biological rationale for the choice of a given definition of menopause.


Assuntos
Neoplasias da Mama/epidemiologia , Menopausa/fisiologia , Fatores Etários , Baltimore/epidemiologia , Viés , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Minnesota/epidemiologia , Razão de Chances , Paridade , Fatores de Risco , Sensibilidade e Especificidade
19.
Am J Trop Med Hyg ; 57(1): 79-84, 1997 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9242324

RESUMO

A survival analysis was performed on data from an endemic area of Bolivia where two populations, natives and highland migrants, were living, to investigate risk factors for onset of cutaneous leishmaniasis (CL) and its mucosal form (MCL). In a first data set (703 subjects with 242 CL patients), significant risk factors for CL were gender, native/migrant status, activity, and home-forest distance. The instantaneous risk of CL increased until adolescence in both populations, and rapidly decreased thereafter. This risk was 3-10 times higher in migrants than in natives until 20 years of age, and became similar thereafter. Environmental and behavioral factors did not seem sufficient to explain this contrast between the two populations, and this evolution with age may suggest differences in the mechanisms involved in the development of individual protection during childhood. In a second data set (446 CL patients with 34 mucosal forms) the native/migrant status was the main factor associated with the onset of mucosal form.


Assuntos
Leishmaniose Cutânea/etiologia , Leishmaniose Mucocutânea/etiologia , Adolescente , Adulto , Fatores Etários , Bolívia/epidemiologia , Criança , Pré-Escolar , Emigração e Imigração , Feminino , Humanos , Lactente , Leishmaniose Cutânea/epidemiologia , Leishmaniose Mucocutânea/epidemiologia , Masculino , Análise Multivariada , Fatores de Risco , Fatores Sexuais
20.
J Palliat Care ; 12(1): 26-30, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8857244

RESUMO

In the course of the inevitable hospitalizations of AIDS patients, many difficult questions concerning curative and palliative approaches to care have to be answered. In order to guide these strategies, we conducted a prospective study to identify those variables which can be easily quantified on admission which might be predictive of patient outcomes. Between 1 June 1990 and 25 April 1991, 140 consecutive hospitalizations of 83 AIDS patients were recorded. Demographic, clinical, and biological data were collected within 48 hours of admission. Probable (p <0.10) or definite (p <0.05) factors contributing to a higher mortality included type of opportunistic infections, serum albumin level, total lymphocyte count, weight, CD4 cell count, and neurological manifestations. In the multivariate proportional hazards model, two factors were significantly and independently predictive of lower survival: body weight less than 90% of ideal body weight and neurologic manifestations. The probability of survival was significantly affected by the number of predictive factors present on admission, and patients were significantly more likely to die when these latter two factors were present concomitantly. These factors might be useful to define the optimal mode of care for hospitalized AIDS patients, considering both patients' wishes and an objective assessment of the prognosis.


Assuntos
Síndrome da Imunodeficiência Adquirida , Expectativa de Vida , Cuidados Paliativos , Adulto , Análise de Variância , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paris , Prognóstico , Estudos Prospectivos , Fatores de Risco
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