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Management of COVID-19 patients experiencing persisting respiratory failure despite corticosteroids remains challenging. Data on high-dose intravenous anakinra (HD-ANK) in this context are lacking. We aimed to investigate the impact of HD-ANK on mortality in COVID-19 patients progressing to non-invasive ventilation (NIV) while receiving corticosteroids. We retrospectively analyzed the impact of HD-ANK on 28-day mortality in individuals hospitalized with COVID-19 necessitating NIV after corticosteroid initiation. A total of 256 patients were identified: 146 received standard-of-care only (SOC), and 110 received HD-ANK+SOC. The groups were well-balanced at baseline. In-hospital mortality at 28 days did not differ between the two groups. HD-ANK is not beneficial in patients with severe COVID-19 deteriorating despite corticosteroids.
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Weight gain following the initiation or the switch of antiretroviral therapy (ART) is well documented and mainly associated with some of the most recent drugs, such as integrase strand transfer inhibitors and tenofovir alafenamide. However, limited data have been published on weight trends in ART-experienced people living with HIV (PLWH) with a long exposure to HIV infection and antiretroviral drugs. In our study, we assessed changes in weight after switching ART among PLWH who reported weight gain under a previous regimen.
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Infecções por HIV , Humanos , Infecções por HIV/tratamento farmacológico , Antirretrovirais/uso terapêutico , Aumento de PesoRESUMO
BACKGROUND: Disseminated Mycobacterium chimaera infection is an emerging disease in people undergone to cardiothoracic surgery, which need to be suspected also with atypical presentations. CASE PRESENTATION: We report the case of a 74-year-old man with fever of unknown origin, purple nodules on both feet and a history of open-heart surgery. Imaging investigations showed an abscess near aortic bioprosthesis but screening for endocarditis resulted negative and pyrexia did not respond to antibiotic therapy. A biopsy of cutaneous lesions showed HHV8-related Kaposi's sarcoma, so bone marrow biopsy was executed with evidence of HHV8 localization. Bone marrow and urine mycobacterial cultures resulted positive for M. chimaera and a specific antimicrobial therapy was started, with apyrexia after 7 weeks. CONCLUSIONS: M. chimaera infection should be always investigated as a possible etiology of fever of unknow origin in people with a history of open-heart surgical intervention, even with negative mycobacterial blood cultures. The possible role of disseminated infection in inducing immunodepression with the occurrence of other opportunistic diseases (such as Kaposi's sarcoma) cannot be excluded.
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Infecções por Mycobacterium não Tuberculosas , Mycobacterium , Sarcoma de Kaposi , Masculino , Humanos , Idoso , Sarcoma de Kaposi/diagnóstico , Sarcoma de Kaposi/patologiaRESUMO
Background: This study's primary aim was to evaluate the impact of thrombotic complications on the development of secondary infections. The secondary aim was to compare the etiology of secondary infections in patients with and without thrombotic complications. Methods: This was a cohort study (NCT04318366) of coronavirus disease 2019 (COVID-19) patients hospitalized at IRCCS San Raffaele Hospital between February 25 and June 30, 2020. Incidence rates (IRs) were calculated by univariable Poisson regression as the number of cases per 1000 person-days of follow-up (PDFU) with 95% confidence intervals. The cumulative incidence functions of secondary infections according to thrombotic complications were compared with Gray's method accounting for competing risk of death. A multivariable Fine-Gray model was applied to assess factors associated with risk of secondary infections. Results: Overall, 109/904 patients had 176 secondary infections (IR, 10.0; 95% CI, 8.8-11.5; per 1000-PDFU). The IRs of secondary infections among patients with or without thrombotic complications were 15.0 (95% CI, 10.7-21.0) and 9.3 (95% CI, 7.9-11.0) per 1000-PDFU, respectively (P = .017). At multivariable analysis, thrombotic complications were associated with the development of secondary infections (subdistribution hazard ratio, 1.788; 95% CI, 1.018-3.140; P = .043). The etiology of secondary infections was similar in patients with and without thrombotic complications. Conclusions: In patients with COVID-19, thrombotic complications were associated with a high risk of secondary infections.
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Ribavirin is an inosine monophosphate dehydrogenase inhibitor with demonstrated activity against coronaviruses, including SARS-CoV-2. Five hospitalized patients with COVID-19 (confirmed by positive tests for SARS-CoV-2) received treatment with ribavirin for inhalation solution (ribavirin aerosol) as part of a compassionate use program. Patients included four men and one woman, with an age range of 29-72 years. Patients were managed according to international and Italian treatment guidelines for COVID-19. In addition, therapy with ribavirin aerosol 100 mg/mL was administered for 30 min twice daily for 6 days (i.e., 12 doses) in all patients. In order to address concerns about a possible increase in viral dispersal with the use of a nebulizer, healthcare providers remained outside the patient room during ribavirin aerosol administration. Pretreatment chest computed tomography (CT) scans showed pseudonodular areas of parenchymal thickening in the upper right lobe with associated ground glass opacities, multiple areas of parenchymal consolidation in both lower lobes with associated ground glass opacities, bilateral parenchymal thickening and multiple associated ground glass areas, or focal ground glass areas in the upper lobes bilaterally, which were almost completely resolved (three patients) or moderately cleared (one patient) on imaging at the end of ribavirin treatment. For a fifth patient, CT scans showed a stable pulmonary picture at the end of ribavirin treatment. No adverse reactions to ribavirin treatment were observed in any of the five patients. All patients recovered fully, and nasopharyngeal swabs obtained after hospital discharge tested negative for SARS-CoV-2. Ribavirin aerosol appears to be efficacious in the treatment of patients with COVID-19. A controlled trial of ribavirin aerosol is ongoing and will provide additional data across a broader patient population.
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BACKGROUND: Very limited data are available on the immunovirological outcomes after 13-valent pneumococcal conjugate vaccine (PCV13) in antiretroviral therapy (ART)-treated patients. The aim of this study was to assess the immune-virological outcomes in HIV-1-infected ART-treated patients on stable virological suppression who underwent pneumococcal conjugate vaccination. METHODS: Retrospective, cohort study on ART-treated HIV-1-infected individuals, age at least 18 years, with three consecutive determinations of HIV-RNA less than 50 copies/ml before the administration of PCV13 (baseline) at San Raffaele Hospital and with at least two HIV-RNA values after vaccination. RESULTS: Overall 1197 patients underwent PCV13 vaccination. During 6-month of follow-up (594 person-years of follow-up, PYFU), 12 confirmed virological failure and 35 viral blips were observed; the overall incidence rate of confirmed virological failure was 2.02 (95% confidence interval: 0.88-3.16) per 100-PYFU and the incidence rate of viral blips was 5.89 (95% confidence interval: 3.94-7.84) per 100-PYFU. Median CD4 cell count change from baseline at 6 months was +10 cells/µl (interquartile range -67, +111; Pâ=â0.0002). Median change in CD4/CD8 ratio was +0.02 (interquartile range -0.06, +0.11; Pâ<â0.001). CONCLUSION: Viral blips and confirmed virological failures were rarely observed in patients on stable virological suppression in the first 6 months following vaccination with PCV13. In addition, no decrease of CD4 cell count and CD4/CD8 ratio was recorded.
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Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/imunologia , Vacinas Pneumocócicas/imunologia , Resposta Viral Sustentada , Carga Viral , Viremia , Adulto , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1 , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Infecções Pneumocócicas/prevenção & controle , Estudos Retrospectivos , Falha de TratamentoRESUMO
OBJECTIVE: To evaluate the 24-week effects on glucose tolerance of switching from a protease inhibitor (PI)-based to an unboosted atazanavir-including regimen in highly pretreated HIV-1 infected subjects with metabolic alterations. DESIGN: Prospective, open-label, single-center, 24-week pilot study. METHODS: Twenty-one subjects underwent an oral glucose tolerance test (OGTT) at baseline (BL) and after 24 weeks of unboosted atazanavir. Insulin sensitivity and beta-cell responsiveness were evaluated on the basis of static and dynamic data; fasting glucose, insulin, C-peptide, triglycerides (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c), TC/HDL-c ratio, CD4+ cell count and HIV-1 RNA were measured. RESULTS: After 24 weeks of unboosted atazanavir, the 120-min glucose level was significantly lower than the one measured at BL (P=0.021); there were no statistically significant differences in the insulin concentration profile. The SI(oral), an OGTT-based index of insulin sensitivity, was significantly higher at week 24 (P=0.017); the indices of first- and second-phase beta-cell responsiveness did not significantly change. There was no significant difference between BL and 24-week fasting glucose, insulin or C-peptide levels, and consequently no change in fasting homeostasis model assessment indices of insulin sensitivity and beta-cell function. There were significant improvements in TG (P=0.009), TC (P=0.0001), LDL-c (P=0.019) and TC/HDL-c ratio (P=0.001), and a similar trend in HDL-c levels (P=0.069). No significant changes in the immunological and virological parameters were detected. CONCLUSIONS: Our results show that switching from a PI-based to an unboosted atazanavir-including regimen leads to a significant improvement in glucose tolerance in highly pretreated HIV-1 infected subjects with metabolic alterations.
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Glicemia/metabolismo , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1 , Oligopeptídeos/uso terapêutico , Piridinas/uso terapêutico , Adulto , Sulfato de Atazanavir , Jejum/sangue , Jejum/metabolismo , Feminino , Teste de Tolerância a Glucose , Inibidores da Protease de HIV/efeitos adversos , Humanos , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos , Projetos Piloto , Estudos Prospectivos , Inibidores de Proteases/uso terapêutico , Piridinas/efeitos adversos , Retratamento , Resultado do TratamentoRESUMO
OBJECTIVE: We compared the immunological and clinical outcomes of lamivudine monotherapy and complete therapy interruption in the treatment of HIV-1-infected patients harbouring lamivudine-resistant virus. METHODS: This 48-week, open-label pilot study randomly assigned HIV-infected patients receiving lamivudine-containing HAART and harbouring the M184V mutation to monotherapy with lamivudine 300 mg once daily (lamivudine group) or the discontinuation of all antiretroviral drugs (TI group). The primary endpoint was the occurrence of immunological or clinical failure; immunological failure was defined as the first report of a CD4 T-cell count less than 350 cells/microl, and clinical failure as the occurrence of a Centers for Disease Control and Prevention grade B or C event. The data were analysed on the basis of the intention-to-treat principle. RESULTS: By week 48, 20 of 29 patients in the TI group (69%; 95% CI 51-83%) and 12 of 29 in the lamivudine group (41%; 95% CI 26-59%) had discontinued the study because of immunological or clinical failure, which was significantly delayed in the lamivudine group (P = 0.018). Only patients in the TI group (6/29, 20.7%) experienced grade 3-4 clinical adverse events at least possibly related to HIV-1 (P = 0.02). The mean decline in CD4 cell percentage, viral rebound and recovery of HIV-1 replication capacity were significantly lower in the lamivudine group. The 24-week virological and immunological response after therapy resumption in patients who prematurely discontinued the study was similar in the two groups. CONCLUSION: In HIV-1-infected patients harbouring a lamivudine-resistant virus, lamivudine monotherapy may lead to a better immunological and clinical outcome than complete therapy interruption.
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Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Lamivudina/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4 , Esquema de Medicação , Farmacorresistência Viral , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/genética , HIV-1/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Projetos Piloto , Falha de Tratamento , Resultado do Tratamento , Carga Viral , Replicação ViralRESUMO
Enfuvirtide (ENF) is the first HIV-1 entry inhibitor used in clinical practice and is currently administered via the subcutaneous route. We here evaluated whether ENF administration leads to a change in humoral parameters, including IgE, possibly related to ENF-associated injection site reactions (ISRs). A 24-week prospective study was conducted in multidrug resistant patients enrolled in the ENF Early Access Program characterized by CD4 counts < or =100 cells/microlitre and no other active antiretroviral drug. Licensed commercial laboratory assays were used to measure the parameters considered in this study. Results are reported as medians (interquartiles IQR). Statistical analyses were performed using Wilcoxon sign rank, Wilcoxon rank sum and Kruskall Wallis tests. Total IgM, IgA and IgG did not change significantly throughout the study. Conversely, a significant increase in IgE was observed in all patients, in those with normal as well as in those with altered IgE at baseline (BL). ISRs such as induration and number of nodules were more frequent in patients with altered BL IgE. IgE increased significantly in all patients, regardless of the different stratifications in their BL CD4 counts. Of note, the ENF-induced increase in CD4 occurred significantly in all patients, independently of their BL IgE levels. The immunological response associated with ENF treatment is accompanied by a selective increase in IgE levels. Determination of IgE could be used in the monitoring ISRs associated with ENE
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Farmacorresistência Viral Múltipla , Proteína gp41 do Envelope de HIV/administração & dosagem , Inibidores da Fusão de HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Imunoglobulina E/sangue , Fragmentos de Peptídeos/administração & dosagem , Adulto , Contagem de Linfócito CD4 , Enfuvirtida , Feminino , Proteína gp41 do Envelope de HIV/efeitos adversos , Proteína gp41 do Envelope de HIV/uso terapêutico , Inibidores da Fusão de HIV/efeitos adversos , Inibidores da Fusão de HIV/uso terapêutico , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/uso terapêuticoRESUMO
The redistribution of mutations related to protease inhibitor (PI) resistance after a PI-sparing regimen in human immunodeficiency virus (HIV)-infected, highly PI-experienced patients was prospectively assessed. Twenty-five patients failing a PI-including regimen were given PI-sparing antiretroviral therapy, and then followed for 24 weeks after PI resumption. Genotyping was performed by direct sequencing before and during the PI-sparing regimen. The median (interquartile range, IQR) baseline CD4+ T-lymphocyte count was 198 (120-255) cells/microl, and the median HIV-RNA level was 82,000 (41,000-300,000) copies/ml. Patients had experienced a median of 4.5 (4-5.25) PIs. The median number of PI mutations was eight (6-9). The PI-sparing regimen consisted of a median of three (3-4) drugs and lasted for a median of 53 (24-67) weeks. At the end of the study, the median number of PI mutations was 6.5 (6-9). The median change in the number of PI mutations was -1 (IQR from -1 to 0). A reduction from baseline was observed in 13 cases (52%); nine (36%) showed no change and three (12%) showed an increased number of PI substitutions. In highly PI-experienced patients, a PI-sparing regimen may lead to a reduction, no change, or increase in the number of PI mutations. The reduction is negligible in most cases.
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Farmacorresistência Viral/genética , Variação Genética , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacologia , Protease de HIV/genética , HIV-1/efeitos dos fármacos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Esquema de Medicação , Quimioterapia Combinada , Genótipo , Infecções por HIV/virologia , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/uso terapêutico , HIV-1/classificação , HIV-1/enzimologia , HIV-1/genética , Humanos , Mutação , RNA Viral/sangue , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/uso terapêuticoRESUMO
Genotypes in nine highly protease inhibitor (PI)-experienced patients were studied before and after lopinavir/ritonavir (LPV/r) treatment. Resistance to amprenavir was the rule both before and after LPV/r treatment. Treatment with LPV/r can select for the 50 V mutation. In this setting, significant differences in the inference of the amprenavir phenotype from genotype were observed when using different algorithms.
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Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Pirimidinonas/uso terapêutico , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Carbamatos , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Furanos , Genótipo , HIV/genética , Infecções por HIV/genética , Humanos , Lopinavir , Masculino , Pessoa de Meia-Idade , Mutação/genética , RNA Viral/sangue , Estudos RetrospectivosRESUMO
OBJECTIVE: To investigate the normalized inhibitory quotient (NIQ) of lopinavir (LPV) as a predictor of 48-week virological responses to a lopinavir/ritonavir (LPV/RTV)-containing regimen in highly treatment-experienced patients. DESIGN: We calculated the NIQ for 59 patients who completed 48 weeks' treatment and assessed the factors predicting a week-48 virological response. METHODS: The NIQ was calculated by dividing each subject's IQ (LPV Ctrough/fold change in LPV susceptibility, as assessed by VirtualPhenotype) by a reference IQ (mean population LPV Ctrough/fold change in LPV IC50, as assessed by VirtualPhenotype). HIV-1 RNA was assessed by NASBA (quantification limit: 80 copies/ml). The general linear model and multiple logistic regression, respectively, were used to estimate the independent predictors of a change in viral load and HIV-1 RNA <80 copies/ml. RESULTS: The median (interquartile range) baseline levels of CD4+ cells and HIV-1 RNA were 251 (141-385) cells/microl and 4.85 (4.49-5.23) log10 copies/ml, respectively. The median NIQ was 2.2 (0.5-14). At week 48, the median decrease in HIV-1 RNA was 1.4 (0.59-2.79) log10 copies/ml (P<0.0001), with 24 subjects (41%) reaching <80 copies/mi. Baseline HIV-1 RNA (P=0.001), CD4+ cells (P=0.002) and NIQ (P=0.0006) independently predicted the week-48 change in viral load, whereas baseline CD4+ cells (P=0.011) and NIQ (P=0.009) independently predicted a week-48 HIV-1 RNA level of <80 copies/ml. CONCLUSION: The LPV NIQ independently predicts virological responses to an LPV/RTV-containing regimen in highly treatment-experienced HIV-1-infected patients.
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Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Pirimidinonas/uso terapêutico , Ritonavir/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Monitoramento de Medicamentos , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/farmacologia , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Lopinavir , Masculino , Testes de Sensibilidade Microbiana , Análise Multivariada , Fenótipo , Pirimidinonas/sangue , Pirimidinonas/farmacologia , Ritonavir/administração & dosagem , Carga ViralAssuntos
Antirretrovirais/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Lamivudina/uso terapêutico , Raltegravir Potássico/uso terapêutico , Antirretrovirais/administração & dosagem , Terapia Antirretroviral de Alta Atividade , Combinação de Medicamentos , HIV-1/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND: In HIV-1-infected patients harbouring the M184V mutation (M184V), lamivudine monotherapy leads to a smaller decrease in CD4 percentages (CD4%) than treatment interruption, possibly due to the reduced fitness of the mutated virus. OBJECTIVE: We assessed whether a minimal dose of a cytidine analogue that is theoretically sufficient to maintain M184V (one emtricitabine tablet once-weekly) may be as effective. STUDY DESIGN: In a proof-of-concept, randomised clinical trial, HIV-1-infected patients with CD4 cells >400/mm(3), failing on lamivudine- or emtricitabine-containing combination antiretroviral therapy (cART), received emtricitabine once-a-week (A), or emtricitabine once-a-day (B), or lamivudine once-a-day (C). The primary endpoint was the proportion of subjects without a 12-week loss in CD4%. The patients resumed cART after 24 weeks or in the case of CD4 cells <350/mm(3). RESULTS: The 38 enrolled patients had similar baseline characteristics across groups. The primary endpoint was reached by 5/13 patients (38.5%) in arm A, 3/13 (23.1%) in arm B, and 3/12 (25%) in arm C (P=0.644), and respectively 4/13 (30.8%), 4/13 (30.8%) and 5/12 (41.7%) had to resume cART within 24 weeks (P=0.805). The immunological changes over 24 weeks were similar in the three groups, but there was a higher median viral rebound in once-weekly treatment recipients (A) than in once-daily (B+C): 0.97 versus 0.52log(10)copies/ml (P=0.033). M184V was maintained in all the participants. CONCLUSIONS: Once-weekly emtricitabine led to a higher viral rebound than once-daily monotherapy, but similar immunological changes, thus suggesting a role of M184V in slowing the decrease in CD4% in treatment failing subjects.
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Fármacos Anti-HIV/uso terapêutico , Desoxicitidina/análogos & derivados , Farmacorresistência Viral , Infecções por HIV/imunologia , Infecções por HIV/virologia , Terapia de Salvação/métodos , Carga Viral , Adulto , Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4 , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Emtricitabina , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Falha de TratamentoRESUMO
The objective of this study was to investigate the mechanisms underlying the virological and immunological changes occurring in failing HIV-1 infected patients undergoing treatment interruption or lamivudine monotherapy (the E-184V Study). Associations were sought between the de-selection of individual reverse transcriptase and protease resistance mutations and replication capacity recovery, HIV-RNA changes, and immunological changes. The replication capacity recovery was defined as the ratio between the replication capacity at weeks 24 or 48, and that measured at baseline. The replication capacity recovery, which was evaluable in 21 patients at week 24 and in 18 at week 48, was significantly higher in the treatment interruption than in the lamivudine group at week 24 (P = 0.002). Forty-eight week replication capacity recovery was greater when the 184V (P = 0.023), the 41L (P = 0.02), or the 215Y mutation (P = 0.037) were deselected at week 12. A greater reduction in the CD4+/CD8+ ratio at week 48 (P = 0.038) was observed as the 184V mutation was deselected and the de-selection of the 184V mutation at week 12 was the only independent predictor of the change of the CD4+/CD8+ ratio at week 48 from baseline at multivariable analysis (F-value = 6.72, P = 0.021). In conclusion, among patients undergoing treatment interruption or lamivudine monotherapy, the recovery of HIV-1 replication capacity was associated with the de-selection of reverse transcriptase mutations. The de-selection of the 184V mutation predicts independently a reduction in the CD4+/CD8+ ratio.
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Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/crescimento & desenvolvimento , HIV-1/genética , Lamivudina/uso terapêutico , Adulto , Substituição de Aminoácidos/genética , Relação CD4-CD8 , Infecções por HIV/imunologia , HIV-1/fisiologia , Humanos , Mutação de Sentido Incorreto , Replicação ViralRESUMO
The genotypic inhibitory quotient (GIQ) is the ratio between drug concentration and the number of resistance mutations. However, as different resistance scores can be calculated for the same protease inhibitor, the ability of a GIQ to predict the virological outcome may vary depending on the resistance score used as the denominator. Forty-four highly treatment-experienced HIV-infected patients failing on their current regimen were treated with a lopinavir/ritonavir-containing combination for at least 48 weeks. Three GIQs were calculated for each patient: the denominator of the first (GIQ-A) was the lopinavir/ritonavir score calculated using the mutations listed by IAS-USA as being related to lopinavir/ritonavir resistance; the denominator of the second (GIQ-B) was the total number of mutations related to resistance to any protease inhibitor as reported by IAS-USA; and the denominator of the third (GIQ-C) was the lopinavir/ritonavir score proposed by Parkin et al. The median (IQR) of the GIQ-A, B, and C was 4.69 (3.83-9.76), 0.97 (0.74-1.62), and 1.02 (0.68-2.52), respectively. At week 48, the median decrease in HIV-RNA was 1.09 (0.32-2.34) log(10) copies/ml (P < 0.0001), with 13 subjects (29.5%) attaining undetectable levels. All of the GIQs independently predicted the change in viral load from baseline and undetectable HIV-RNA at week 48. The partial R(2) of GIQ-C was greater than that of GIQ-B, which was greater than that of GIQ-A. All of the GIQs were independent predictors of the 48-week virological response. The predictive value of the GIQ for lopinavir/ritonavir may vary depending on the algorithm used to score drug resistance.
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Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , HIV-1/efeitos dos fármacos , Pirimidinonas/farmacocinética , Ritonavir/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Quimioterapia Combinada , Genótipo , Infecções por HIV/virologia , Protease de HIV/efeitos dos fármacos , Protease de HIV/genética , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/classificação , HIV-1/genética , Humanos , Lopinavir , Análise Multivariada , Valor Preditivo dos Testes , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/farmacologia , Ritonavir/uso terapêutico , Resultado do TratamentoRESUMO
Patients infected with HIV-1 with more than 1000 HIV-1 RNA copies/mL, who were genotyped within 3 months before starting stavudine and treated for at least 3 months with a stable stavudine-containing highly active antiretroviral therapy, were selected from our database to identify the determinants of response to stavudine. Nonresponse was defined as a failure to achieve HIV-1 RNA level of less than 400 copies/mL or a reduction of more than 2 log10 by week 12. Univariate logistic analysis was used to elicit the failure-associated reverse transcriptase mutations (scored 1 to develop a genotype score). Eighty-one patients were eligible for the analysis, including 75 (93%) who previously received zidovudine. Thirty-five (43%) were nonresponders. Univariate logistic analysis revealed the following failure-associated mutations: 41L (P = 0.0001), 44D (P = 0.02), 118I (P = 0.0006), 184V (P = 0.04), 210W (P = 0.0004), and 215Y (P = 0.002) for a median stavudine score of 2. Failure was observed in 7 (18.9%) of 37 patients with a score less than 2, compared with 28 (63.6%) of 44 patients with a score of 2 or greater (P < 0.0001). The multivariable analysis showed that the 118I mutation (P = 0.04) was the only independent genotypic predictor of failing on a stavudine- containing highly active antiretroviral therapy.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , Mutação de Sentido Incorreto , Estavudina/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade , Feminino , Genes pol , Infecções por HIV/virologia , Transcriptase Reversa do HIV/efeitos dos fármacos , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Terapia de Salvação/métodos , Análise de Sequência de DNA , Estatística como Assunto , Estavudina/administração & dosagem , Estavudina/farmacologia , Falha de Tratamento , Carga ViralRESUMO
OBJECTIVES: The aim of this study was to evaluate the correlation between liver function markers (necrosis and cholestasis) and plasma lopinavir levels in a cohort of HIV-infected patients treated with lopinavir and ritonavir. PATIENTS AND METHODS: The blood samples for determining steady-state C(trough) lopinavir levels and analysing liver function were drawn from fasting patients. Steady-state C(trough) lopinavir levels, liver function and immuno-virological markers were assessed on the same day. Plasma lopinavir and ritonavir levels were determined by means of high-performance liquid chromatography. RESULTS: One hundred and forty-nine patients were included in the analysis [57 were HCV co-infected (34%) and 10 were HBV co-infected (6.7%)]; they had been treated with lopinavir/ritonavir for a median of 232 days (range 132-282). All patients received lopinavir/ritonavir [400/100 mg twice daily or 533/133 mg twice daily if amprenavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI) was part of therapy] and concomitant therapy with NRTI(s). Median (interquartile) lopinavir trough levels were 6391 ng/mL (4121-8726), 5662 (3585-8893) and 6819 ng/mL (5324-8726) in the patients with HIV alone and those with HIV/HCV (or HBV) co-infection, respectively (P = not significant). Univariate analysis showed a significant association between the cholestasis markers and C(trough) lopinavir level. Multivariate analysis selected only gamma glutamyltranspeptidase (GGT) (OR = 1.010, 95% CI: 1.002-1.021) as being independently associated with plasma lopinavir levels of >6425 ng/mL; alkaline phosphatase (OR = 1.004, 95% CI: 1.000-1.010; P = 0.08) and total bilirubin (OR = 3.118, 95% CI: 0.980-11.715; P = 0.07) were not associated. CONCLUSIONS: Elevated lopinavir concentrations are associated with raised GGT.
Assuntos
Fármacos Anti-HIV/sangue , Colestase/sangue , Colestase/complicações , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Pirimidinonas/sangue , Adulto , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Fármacos Anti-HIV/farmacocinética , Bilirrubina/sangue , Biomarcadores/análise , Colestase/induzido quimicamente , Colestase/metabolismo , Feminino , Infecções por HIV/sangue , Humanos , Lopinavir , Masculino , Pirimidinonas/farmacocinética , Pirimidinonas/uso terapêutico , Estudos Retrospectivos , gama-Glutamiltransferase/sangue , gama-Glutamiltransferase/metabolismoRESUMO
The human immunodeficiency virus type 1 (HIV-1) fusion inhibitor enfuvirtide has recently been introduced into clinical practice and has exhibited efficient anti-HIV-1 activity in combination with other antiretroviral agents. In the present study, we addressed the effect of long-term treatment with enfuvirtide on the intrahost evolution of HIV-1. The genotype and phenotype patterns and the relative replication capacity (rRC) of enfuvirtide-resistant HIV-1 mutants were evaluated in samples from 11 subjects (7 virological nonresponders and 4 responders) who received the compound for more than 1 year in combination with different regimens. Selection of one or more mutations clustering in a sequence (amino acids 36 to 45) of the gp41 N-terminal heptad repeat was observed in samples from the seven virological nonresponders but not in those from responders. In two subjects who discontinued enfuvirtide, reversion of the resistant genotype was detected within 3 months. Recombinant clones bearing mutated gp41 sequences displayed reduced susceptibilities to enfuvirtide, with the 50% inhibitory concentrations (IC(50)s) ranging from 0.6 to 12.8 microg/ml, whereas the IC(50) for isolates with baseline sequences was 0.013 +/- 0.010 microg/ml. Interestingly, long-term monitoring of resistant variants provided evidence that ongoing adaptation to the drug is paralleled by phenotypic changes. A limited drop in the rRC in the absence of drug was observed for clones from four of the seven nonresponders bearing mutations associated with resistance. Overall, the data indicate that the different genotype patterns associated with a detectable degree of HIV-1 resistance to enfuvirtide generated during long-term treatments are characterized by a substantially low genetic barrier, possible ongoing adaptation with increased degrees of resistance, and limited influence on the viral rRC.