RESUMO
Neural activity and learning lead to myelin sheath plasticity in the intact central nervous system (CNS), but this plasticity has not been well-studied after CNS injury. In the context of spinal cord injury (SCI), demyelination occurs at the lesion site and natural remyelination of surviving axons can take months. To determine if neural activity modulates myelin and axon plasticity in the injured, adult CNS, we electrically stimulated the contralesional motor cortex at 10 Hz to drive neural activity in the corticospinal tract of rats with sub-chronic spinal contusion injuries. We quantified myelin and axonal characteristics by tracing corticospinal axons rostral to and at the lesion epicenter and identifying nodes of Ranvier by immunohistochemistry. Three weeks of daily stimulation induced very short myelin sheaths, axon branching, and thinner axons outside of the lesion zone, where remodeling has not previously been reported. Surprisingly, remodeling was particularly robust rostral to the injury which suggests that electrical stimulation can promote white matter plasticity even in areas not directly demyelinated by the contusion. Stimulation did not alter myelin or axons at the lesion site, which suggests that neuronal activity does not contribute to myelin remodeling near the injury in the sub-chronic period. These data are the first to demonstrate wide-scale remodeling of nodal and myelin structures of a mature, long-tract motor pathway in response to electrical stimulation. This finding suggests that neuromodulation promotes white matter plasticity in intact regions of pathways after injury and raises intriguing questions regarding the interplay between axonal and myelin plasticity.
Assuntos
Medula Cervical , Contusões , Traumatismos da Medula Espinal , Ratos , Animais , Bainha de Mielina/metabolismo , Medula Cervical/patologia , Traumatismos da Medula Espinal/metabolismo , Axônios/patologia , Contusões/metabolismo , Contusões/patologia , Medula Espinal/metabolismoRESUMO
The global spread of non-tuberculous mycobacteria (NTM) may be due to HIV/AIDS and other environmental factors. The symptoms of NTM and tuberculosis (TB) disease are indistinguishable, but their treatments are different. Lack of research on the epidemiology of NTM infections has led to underestimation of its prevalence within TB endemic countries. This study was designed to determine the prevalence and clinical characteristics of pulmonary NTM in Bamako. A cross-sectional study which include 439 suspected cases of pulmonary TB. From 2006 to 2013 a total of 332 (76%) were confirmed to have sputum culture positive for mycobacteria. The prevalence of NTM infection was 9.3% of our study population and 12.3% of culture positive patients. The seroprevalence of HIV in NTM group was 17.1%. Patients who weighed <55 kg and had TB symptoms other than cough were also significantly more likely to have disease due to NTM as compared to those with TB disease who were significantly more likely to have cough and weigh more than 55 kg (OR 0.05 (CI 0.02-0.13) and OR 0.32 (CI 0.11-0.93) respectively). NTM disease burden in Bamako was substantial and diagnostic algorithms for pulmonary disease in TB endemic countries should consider the impact of NTM.
Assuntos
Soroprevalência de HIV , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Micobactérias não Tuberculosas/isolamento & purificação , Adolescente , Adulto , Idoso , Coinfecção/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Mali/epidemiologia , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Prevalência , Fatores de Risco , Estudos Soroepidemiológicos , Adulto JovemRESUMO
BACKGROUND: Although Drug resistance tuberculosis is not a new phenomenon, Mali remains one of the "blank" countries without systematic data. METHODS: Between 2006 and 2014, we enrolled pulmonary TB patients from local TB diagnostics centers and a university referral hospital in several observational cohort studies. These consecutive patients had first line drug susceptibility testing (DST) performed on their isolates. A subset of MDR was subsequently tested for second line drug resistance. RESULTS: A total of 1186 mycobacterial cultures were performed on samples from 522 patients, including 1105 sputa and 81 blood samples, yielding one or more Mycobacterium tuberculosis complex (Mtbc) positive cultures for 343 patients. Phenotypic DST was performed on 337 (98.3%) unique Mtbc isolates, of which 127 (37.7%) were resistant to at least one drug, including 75 (22.3%) with multidrug resistance (MDR). The overall prevalence of MDR-TB was 3.4% among new patients and 66.3% among retreatment patients. Second line DST was available for 38 (50.7%) of MDR patients and seven (18.4%) had resistance to either fluoroquinolones or second-line injectable drugs. CONCLUSION: The drug resistance levels, including MDR, found in this study are relatively high, likely related to the selected referral population. While worrisome, the numbers remained stable over the study period. These findings prompt a nationwide drug resistance survey, as well as continuous surveillance of all retreatment patients, which will provide more accurate results on countrywide drug resistance rates and ensure that MDR patients access appropriate second line treatment.
Assuntos
Antituberculosos/farmacologia , Infecções por HIV/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Pulmonar/epidemiologia , Adolescente , Adulto , Antituberculosos/uso terapêutico , Estudos de Coortes , Farmacorresistência Bacteriana Múltipla , Feminino , Fluoroquinolonas/farmacologia , Infecções por HIV/microbiologia , Humanos , Masculino , Mali/epidemiologia , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Prevalência , Retratamento , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Adulto JovemRESUMO
Background The role of viral load level and/or CD4 (Cluster of differentiation 4) cell count in the aetiopathogenesis of hearing loss in HIV infection is unclear. Therefore, we investigated the relationship between CD4 cell counts, viral load and hearing threshold of HIV (Human immunodeficiency virus) infected adults. METHODS: This cohort audiometric study involved consecutive HIV-infected and HIV-uninfected adults as controls. Clinical data relating to hearing loss, HIV status, and highly -active antiretroviral therapy (HAART) were obtained. Audiornetric evaluation was performed. The most recent CD4 cell counts and RNA viral load-of HIV-infected participants were obtained from clinic records. RESULTS: There were 299(66.7%) HIV-infected adults and 149(33.3%) controls with mean age of 39.64± 12.45 years and 39.60±12.45 years respectively (p=0.98). In both groups, there were more participants with left hearing loss. Mild to profound hearing loss was found in 65.9% HIV- infected participants and 53.7% controls. Majority (86.3%) of the HIV-infected participants were on HAART. The mean CD4 cell count was 654.58±289.15 in 41 HIV-infected participants not on HAART and 523.95±300.17 in 258 participants on HAART (p=0.01). Majority,- 197 (62%) HIV- infected participants with hearing loss had CD4 cell count ≤200 cells/mm3. Higher viral load significantly correlated with low CD4 cell counts (p<0.0 1; r=0. 18) and low CD4 cell count significantly correlated with high hearing threshold (pAssuntos
Terapia Antirretroviral de Alta Atividade
, Infecções por HIV
, Perda Auditiva
, Adulto
, Terapia Antirretroviral de Alta Atividade/efeitos adversos
, Terapia Antirretroviral de Alta Atividade/métodos
, Audiometria/métodos
, Contagem de Linfócito CD4
, Feminino
, Infecções por HIV/complicações
, Infecções por HIV/diagnóstico
, Infecções por HIV/epidemiologia
, Infecções por HIV/virologia
, Perda Auditiva/diagnóstico
, Perda Auditiva/epidemiologia
, Perda Auditiva/etiologia
, Humanos
, Masculino
, Pessoa de Meia-Idade
, Nigéria/epidemiologia
, Estatística como Assunto
, Carga Viral
RESUMO
OBJECTIVES: Studies have shown the importance of having a high protein-binding-adjusted inhibitory quotient (IQ) for protease inhibitors (PIs) boosted with ritonavir. The objective of this study was to explore the virological response when combination atazanavir/ritonavir was administered to treatment-nai¨ve patients. METHODS: Protein-binding-adjusted IQs were calculated in 100 treatment-nai¨ve patients initiating therapy with atazanavir 300 mg/ritonavir 100 mg plus two nucleoside reverse transcriptase inhibitors. RESULTS: The median atazanavir trough level was 635 ng/mL [interquartile range (IQR) 342-1000] and the median atazanavir protein-binding-adjusted IQ was 45 (IQR 24-71). Eighty-four per cent of patients had a successful virological response, and those who failed did not develop resistance. The IQ for boosted atazanavir is high, resulting in rare treatment failure without resistance mutations. CONCLUSIONS: This study showed that the protein-binding-adjusted IQ of atazanavir is close to those measured for lopinavir and darunavir used once daily in first-line treatment. Finally the selection of resistance in the case of virological failure (plasma viral load 4400 HIV-1 RNA copies/mL) to atazanavir/ritonavir used in first-line therapy seems uncommon, as it is for all boosted PIs.
Assuntos
Infecções por HIV/metabolismo , Inibidores da Protease de HIV/farmacocinética , Oligopeptídeos/farmacocinética , Piridinas/farmacocinética , Ritonavir/farmacocinética , Adulto , Idoso , Sulfato de Atazanavir , Proteínas Sanguíneas/metabolismo , Farmacorresistência Viral Múltipla , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Ligação Proteica , Piridinas/administração & dosagem , Ritonavir/administração & dosagem , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
BACKGROUND: Non-conversion on auramine smear microscopy indicates a lack of treatment response, possibly associated with initial rifampicin-resistant tuberculosis (RR-TB). However, dead bacteria still stain positive and may be detected. Fluorescein diacetate smear microscopy (FDA) shows live mycobacteria only. Therefore, we studied the potential of 2-month (2M) FDA for the identification of initial RR-TB.METHODS: Between 2015 and 2018, we enrolled new smear-positive pulmonary TB patients from five local centres in Bamako, Mali. After baseline screening, sputum samples were collected at 1M, 2M, 5M and 18M. We used rpoB sequencing to identify initial RR-TB.RESULTS: Of 1359 patients enrolled, 1019 (75%) had rpoB sequencing results. Twenty-six (2.6%, 95%CI: 1.7-3.7) had mutations conferring rifampicin resistance. Most frequent rpoB mutations were located at the codons Asp435Val (42.4%) and Ser450Leu (34.7%). Among patients with initial RR-TB, 72.2% were FDA-negative at 2M (P = 0.2). The positive and negative predictive value of 5M FDA for culture-based failure was respectively 20.0% and 94.7%.CONCLUSION: FDA did not identify the majority of patients with initial RR-TB or culture-based failure. As the full spectrum of mutations identified on sequencing was identified using Xpert, our data support its rapid universal implementation in Mali.
Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Farmacorresistência Bacteriana , Fluoresceínas , Humanos , Mali , Técnicas de Diagnóstico Molecular , Mycobacterium tuberculosis/genética , Rifampina , Sensibilidade e Especificidade , EscarroRESUMO
INTRODUCTION: In recent years, children born to HIV-infected mothers have been receiving antiretroviral treatment (ART) with limited or no virologic monitoring, which increases the likelihood of development and accumulation of drug resistance mutations, which itself may limit the effectiveness of future ART. The objective of this study was to evaluate the prevalence of resistance mutations in children infected with HIV-1 experiencing virological failure to second-line ART in the Pediatric Department of Gabriel Touré Hospital in Mali. METHODS: Children aged from 5 to 18 infected with HIV-1 on second-line antiretroviral therapy and whose viral load was greater than 1000 copies/mL after observance reinforcement were enrolled. The protease and reverse transcriptase genes were sequenced with ViroSeq®. The results were interpreted according to the last version of the Stanford algorithm in 2018. The study was approved by the Ethics Committee of the Faculty of Medicine and Dentistry, University of Sciences, Techniques and Technologies of Bamako (Mali). RESULTS: Of 216 children, 33 (15.3%) who had a viral load (VL)>1000 copies/mL in second line were recruited and included in the study. The median plasma viral load was 77,000 copies/mL [IQR (28,000-290,000)] and the median CD4 cell count was 310 cells/mm3 [IQR (152-412)]. The median age was 12 years; 48.5% of patients were treated with a combination of stavudine/lamivudine/nevirapine (Triomune®) for first-line treatment and 60.6% with abacavir/lamivudine/lopinavir/ritonavir for the second-line ART. The median treatment duration was 8.5 years [range, 3-13]. Of the 33 children whose treatment failed, the predominant HIV-1 subtype was CRF02_AG (66.7%). The prevalence of resistance to ART classes was 60.61% (20/33) to nucleoside reverse transcriptase inhibitors (NRTIs), 54.51% (18/33) to nonnucleoside reverse transcriptase inhibitors (NNRTIs), and 51.52% (17/33) to protease inhibitors (PIs). Of the patients studied, 90.9% were exposed to lopinavir/ritonavir (LPV/r) but only 15.2% (5/33) developed resistance to LPV/r. CONCLUSIONS: This study demonstrated that LPV/r remains active in most patients after second-line ART failure. In children whose second-line ART fails, particular attention should be paid to their ART and adherence history when considering the next treatment option.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Adolescente , Fármacos Anti-HIV/farmacologia , Criança , Pré-Escolar , Estudos Transversais , Esquema de Medicação , Combinação de Medicamentos , Feminino , Infecções por HIV/virologia , HIV-1/genética , Humanos , Masculino , Mali , Mutação , Falha de Tratamento , Carga Viral/efeitos dos fármacosRESUMO
INTRODUCTION: Diabetes Mellitus (DM) increases worldwide, mostly in low- and middle-income countries. In Mali, the prevalence in the adult population is estimated at 1.8%, but tuberculosis (TB) patients are not systematically screened. The goal of our study was to determine the prevalence of DM among newly diagnosed TB patients. METHODS: We conducted a cross sectional study and a pilot prospective cohort study in four health centers in Bamako. All patients underwent fasting capillary-blood glucose (FCBG) test at Day 0, and repeated after one-week of TB treatment. Venous FBG test was performed for discrepancies between the two FCBG results. Thereafter, FCBG was performed for pilot study at month-2 (M2) and M5 of TB treatment. RESULTS: Two hundred and one patients were enrolled in this study. Impaired fasting blood glucose was identified in 17 (8.5%), of whom 11 (5.5%) had DM (VFBG >7â¯mmol/L). Among patients with DM, seven (63.6%) had successful TB treatment outcome, versus 142 (74.7%) of those without DM (pâ¯=â¯0.64), and (OR: 1.69, 95%CI 0.47-6.02). CONCLUSION: The prevalence of DM among TB patients in Bamako exceeds that of the general population and screening at TB diagnosis suffices to identify those with DM. Systematic screening of both diseases will allow better treatment.
RESUMO
INTRODUCTION: Measurement of immuno-hematological parameters has been historically helpful in the diagnosis and treatment monitoring of many infectious diseases and cancers. However, these parameters have not yet been established in many developing countries where patient care strongly relies on such low-cost tests. This study describes the immuno-hematological parameter ranges for Malian healthy adults. METHODS: A cross sectional study was conducted from August 2004 to May 2013. We included 213 healthy volunteers (173 male and 40 female), aged between 18-59 years. Median, 2.5 and 97.5 percentile ranges for each immuno-hematological parameter are presented. RESULTS: In our study population, the hematological parameters' ranges were mostly different to the universal established ranges. We found in our population a Median white blood cell (WBC) count of 5200 cells/µL [3237.5-11900], Red Blood Cell (RBC) count of 4.94 10^6 [3.56-6.17], hemoglobin (Hb) of 14.2 g/dL [12.2-17.38], platelet count (Plt) of 275 10^3/µL [145.4-614.4], lymphocytes 2050/µL [1200-3800], neutrophils 2200/µL [1040-6220]; monocytes 200/µL [100-660]; eosinophils 131/µL [0-1026]; CD4 902 cells/µL [444-1669] and CD8 485 cells/µL [0-1272]. We found significant gender differences in RBC, Hb level and MPV. However, RBC and Hb were higher in males median values compared to females (median values) (p<0.001), whereas the Mean platelet volume lower values (MPV) in males than females (P<0.047). The hemoglobin level for some West African countries (Mali, Burkina Faso, Togo, and Nigeria) ranged from 13.5 to 15.1 g/dL for males and 12 to 13 g/dL for females. However in East and Southern Africa, the values were anywhere from 14.1 to 16.1 for males and 11.2 to 14.4 for females. CONCLUSION: Our data may help physicians to better define hematological abnormalities in patients. They may also be used to define new "normal hematological values" in Malian population or in the whole West African population.
RESUMO
OBJECTIVES: In Mali early detection and treatment of multidrug-resistant tuberculosis (MDR-TB) are still challenging due to the cost, time and/or complexity associated with regular tests. Microscopic Observation Drug Susceptibility (MODS) is a low-cost assay validated by WHO in 2010. It is a liquid-culture-based assay to detect the 'cording' characteristic of Mycobacterium tuberculosis complex and to assess susceptibility to both isoniazid and rifampicin defining multidrug-resistant tuberculosis (MDR-TB). In this study we aimed to evaluate the performance of MODS as diagnostic tool compared with a validated method-Mycobacteria Growth Indicator Tube/Antimicrobial Susceptibility Testing/Streptomycin, Isoniazid, Rifampicin and Ethambutol (MGIT/AST/SIRE). METHODS AND RESULTS: Between January 2010 and October 2015 we included 98 patients with suspected TB in an observational cohort study. The sensitivity and specificity of MODS assay for detecting TB were respectively 94.12% and 85.71% compared with the reference MGIT/7H11 culture, with a Cohen κ coefficient of 0.78 (95% CI 0.517-1.043). The median time to culture positivity for MODS assay and MGIT (plus interquartile range, IQR) was respectively 8 days (IQR 5-11) and 6 days (IQR 5-6). In detecting patients with MDR-TB, the sensitivity and specificity of MODS assay were respectively 100% and 95.92%. The positive predictive value and negative predictive value were, respectively, 66.7% and 100%. The median turnaround times for obtaining MDR-TB results using MODS assay and MGIT/AST/SIRE was respectively 9 days and 35 days. Hence, the MODS assay rapidly identifies MDR-TB in Mali compared with the MGIT/AST/SIRE. CONCLUSION: As an easy, simple, fast and affordable method, the MODS assay could significantly improve the management of TB.
Assuntos
Antituberculosos/farmacologia , Testes de Sensibilidade Microbiana/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/ultraestrutura , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Adolescente , Adulto , Estudos de Coortes , Diagnóstico Precoce , Etambutol/farmacologia , Feminino , Humanos , Isoniazida/farmacologia , Masculino , Mali , Microscopia/métodos , Pessoa de Meia-Idade , Estudos Prospectivos , Rifampina/farmacologia , Sensibilidade e Especificidade , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Adulto JovemRESUMO
BACKGROUND: The 2NN Study was a randomised comparison of the non-nucleoside reverse-transcriptase inhibitors (NNRTI) nevirapine and efavirenz. METHODS: In this multicentre, open-label, randomised trial, 1216 antiretroviral-therapy-naive patients were assigned nevirapine 400 mg once daily, nevirapine 200 mg twice daily, efavirenz 600 mg once daily, or nevirapine (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine, for 48 weeks. The primary endpoint was the proportion of patients with treatment failure (less than 1 log(10) decline in plasma HIV-1 RNA in the first 12 weeks or two consecutive measurements of more than 50 copies per mL from week 24 onwards, disease progression [new Centers for Disease Control and Prevention grade C event or death], or change of allocated treatment). Analyses were by intention to treat. FINDINGS: Treatment failure occurred in 96 (43.6%) of 220 patients assigned nevirapine once daily, 169 (43.7%) of 387 assigned nevirapine twice daily, 151 (37.8%) of 400 assigned efavirenz, and 111 (53.1%) of 209 assigned nevirapine plus efavirenz. The difference between nevirapine twice daily and efavirenz was 5.9% (95% CI -0.9 to 12.8). There were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per mL at week 48 (p=0.193) or the increases in CD4-positive cells (p=0.800). Nevirapine plus efavirenz was associated with the highest frequency of clinical adverse events, and nevirapine once daily with significantly more hepatobiliary laboratory toxicities than efavirenz. Of 25 observed deaths, two were attributed to nevirapine. INTERPRETATION: Antiretroviral therapy with nevirapine or efavirenz showed similar efficacy, so triple-drug regimens with either NNRTI are valid for first-line treatment. There are, however, differences in safety profiles. Combination of nevirapine and efavirenz did not improve efficacy but caused more adverse events.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1 , Nevirapina/administração & dosagem , Oxazinas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Alcinos , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas , Ciclopropanos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Humanos , Masculino , Nevirapina/efeitos adversos , Oxazinas/efeitos adversos , RNA Viral/sangue , Inibidores da Transcriptase Reversa/efeitos adversos , Falha de TratamentoRESUMO
Data for the force necessary to fracture the isolated calvaria (skull cap) are not available in the extant literature. Twenty dry adult calvaria were tested to failure quasistatically at the vertex using a 15-kN load cell. The forces necessary to fracture or cause diastasis of calvarial sutures were then documented and gross examination of the specimens made. Failure forces had a mean measurement of 2772 N. Initial fractures did not cross suture lines. Prior to complete destruction of the calvaria there were 7 specimens in which all sutures of the calvaria became diastatic, 6 specimens in which the calvaria became diastatic along only the coronal sutures, 2 specimens in which the calvaria became diastatic along only the sagittal suture and 5 specimens in which there were diagonal linear parietal bone fractures. Our hopes are that these data may contribute to the structural design of more safer protective devices for use in our society, assist in predicting injury and aid in the construction of treatment paradigms.
Assuntos
Fraturas Cranianas , Crânio/anatomia & histologia , Adulto , Fenômenos Biomecânicos , Suturas Cranianas/patologia , Traumatismos Craniocerebrais/prevenção & controle , Humanos , Crânio/patologia , Estresse MecânicoRESUMO
OBJECTIVE: To document response to foscarnet salvage therapy in patients with cytomegalovirus (CMV) retinitis who are intolerant of or resistant to ganciclovir. METHODS: Patients with AIDS and CMV retinitis who had documented hematologic intolerance or resistance to ganciclovir therapy received an induction course of foscarnet, 60 mg/kg every 8 h for 14 days, and subsequent chronic maintenance foscarnet therapy at a daily dose of 60, 90 or 120 mg/kg/day. The first 87 patients were randomly assigned to receive maintenance foscarnet at a dose of 60 or 90 mg/kg/day; all subsequent patients were assigned a maintenance dose of 120 mg/kg/day. RESULTS: A total of 156 evaluable patients were enrolled. Median time to retinitis progression and survival did not differ significantly among groups assigned to different maintenance foscarnet doses. Among patients with retinitis progression documented ophthalmologically occurring at < or = 2 week intervals, despite optimal doses of ganciclovir, time to progression on foscarnet therapy was a median 8 weeks at all doses studied. By dose assignment, there were no significant differences in serious drug-associated toxicity, although trends toward increased renal and hypocalcemic adverse events were observed at higher maintenance doses. CONCLUSION: In patients intolerant of ganciclovir, salvage foscarnet therapy resulted in a longer time to retinitis progression than reported previously in historic controls who terminated ganciclovir therapy. In patients who exhibited clinical resistance to ganciclovir, foscarnet appeared to have efficacy in controlling retinitis. No significant differences in either efficacy or toxicity were observed in the range of foscarnet maintenance doses studied.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Retinite por Citomegalovirus/tratamento farmacológico , Foscarnet/uso terapêutico , Ganciclovir/uso terapêutico , Terapia de Salvação , Infecções Oportunistas Relacionadas com a AIDS/complicações , Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Adolescente , Adulto , Idoso , Retinite por Citomegalovirus/complicações , Retinite por Citomegalovirus/mortalidade , Resistência Microbiana a Medicamentos , Feminino , Foscarnet/efeitos adversos , Ganciclovir/efeitos adversos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To assess the incidence of Pneumocystis carinii pneumonia (PCP) after discontinuation of either primary or secondary prophylaxis. DESIGN: This was a prospective, non-randomized, non-blinded study. SETTING: Twenty-five University-based AIDS Clinical Trials Group units. PARTICIPANTS: Participants either had a CD4 cell count < or = 100 x 106/l at any time in the past and no history of confirmed PCP (group I; n = 144), or had a confirmed episode of PCP > or = 6 months prior to study entry (group II; n = 129). All subjects had sustained CD4 cell counts > 200 x 106/l in response to antiretroviral therapy. INTERVENTIONS: Subjects discontinued PCP prophylaxis within 3 months or at the time of study entry. Evaluations for symptoms of PCP and CD4 cell counts were performed every 8 weeks. Prophylaxis was resumed if two consecutive CD4 cell counts were < 200 x 106/l. MAIN OUTCOME MEASURE(S): The main outcome was development of PCP. RESULTS: No cases of PCP occurred in 144 subjects (median follow-up, 82 weeks) in group I or in the 129 subjects (median follow-up, 63 weeks) in group II (95% upper confidence limits on the rates of 1.3 per 100 person-years and 1.96 per 100 person-years for groups I and II, respectively). Eight subjects (five in group I and three in group II) resumed PCP prophylaxis after two consecutive CD4 cell counts < 200 x 106/l. CONCLUSIONS: The risk of developing initial or recurrent PCP after discontinuing prophylaxis is low in HIV-infected individuals who have sustained CD4 cell count increases in response to antiretroviral therapy. Neither lifelong primary nor secondary PCP prophylaxis is necessary.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Antifúngicos/administração & dosagem , Infecções por HIV/imunologia , Pneumonia por Pneumocystis/prevenção & controle , Adulto , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Estudos ProspectivosRESUMO
OBJECTIVE: Comparison of stavudine (d4T), didanosine (ddI) and indinavir (IDV) with zidovudine (ZDV), lamivudine (3TC) and IDV in HIV-1 infected patients. DESIGN: Randomized, open-label. SETTING: Fourteen HIV Clinical Research Centers. PATIENTS: Two-hundred and five patients with less than 4 weeks antiretroviral treatment, naive to 3TC and protease inhibitors and with CD4 cell counts > or = 200 x 10(6)/l and plasma HIV-1 RNA levels > or = 10,000 copies/ml. INTERVENTIONS: Stavudine 40 mg and ddI 200 mg twice daily plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h or 300 mg twice daily, 3TC 150 mg twice daily plus IDV. MAIN OUTCOME MEASURES: The proportion of patients with plasma HIV-1 RNA levels < 500 copies/ml and < or = 50 copies/ml and changes in CD4 cell counts were compared. RESULTS: In an analysis of the primary endpoint, 61% of patients on d4T + ddI + IDV and 45% of patients on ZDV + 3TC + IDV had all HIV-1 RNA values obtained between weeks 40 and 48 < 500 copies/ml [95% confidence interval (CI) for the difference between proportions, 1.7-30.3%; P = 0.038]. In an intent-to-treat analysis, the percentage of all patients randomized with all HIV-1 RNA levels < 500 copies/ml between 40 and 48 weeks were 53% for the d4T + ddI + IDV arm and 41% for the ZDV + 3TC + IDV arm (95% CI, -1.4% to 25.7%; P = 0.068). At 48 weeks 41% and 35% were < or = 50 copies/ml for the stavudine- and ZDV-containing arms respectively (P > 0.2). The median time-weighted average increases in CD4 cells count over 48 weeks were 150 x 10(6)/l cells for the d4T arm and 106 x 10(6)/l cells for the ZDV arm (P= 0.001). The occurrence of serious adverse events was not significantly different between arms. CONCLUSION: The combination of stavudine, ddl and IDV resulted in potent antiretroviral effects over a 48-week period, comparable or superior to zidovudine, 3TC and IDV supporting the use of stavudine, ddI and a protease inhibitor as an initial antiretroviral treatment.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Indinavir/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adolescente , Adulto , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Didanosina/efeitos adversos , Didanosina/uso terapêutico , Didesoxinucleosídeos/efeitos adversos , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/efeitos adversos , HIV-1 , Humanos , Indinavir/efeitos adversos , Lamivudina/efeitos adversos , Lamivudina/uso terapêutico , Masculino , Inibidores da Transcriptase Reversa/efeitos adversos , Estavudina/efeitos adversos , Estavudina/uso terapêutico , Timidina/análogos & derivados , Carga Viral , Zidovudina/efeitos adversos , Zidovudina/uso terapêuticoRESUMO
BACKGROUND: Protease inhibitor-containing antiretroviral therapy for the treatment of HIV-1 infection is associated with elevated triglyceride and low-density lipoprotein (LDL)-cholesterol levels which may expose patients to an increased risk of coronary artery disease (CAD). We report the lipid and lipoprotein profiles of a representative subset of treatment-naive patients included in the Atlantic Study. This study compares patients treated with stavudine and didanosine plus the random addition of either the non-nucleoside reverse transcriptase inhibitor nevirapine (NVP), the protease inhibitor indinavir or the nucleoside reverse transcriptase inhibitor lamivudine. METHODS: Lipids and lipoproteins were quantified from prospectively collected and cryopreserved plasma samples obtained at weeks 0, 6 and 24. RESULTS: We observed a striking increase in high-density lipoprotein (HDL)-cholesterol (49%), apolipoprotein AI (19%), lipoprotein AI (38%) and HDL particle size (3%) in the NVP-treated patients (n = 34) at week 24. Much less pronounced changes in these parameters were seen to a similar extent both in patients receiving lamivudine (n = 39) and indinavir (n = 41). LDL-cholesterol also increased significantly both in the NVP and indinavir arms, but only in the NVP arm was this offset by a significant reduction (14%) in total over HDL-cholesterol ratio. Using a multivariate linear regression model, adjusting for CD4 cell count and plasma HIV RNA both at baseline and during treatment, randomization to the NVP-containing arm remained significant in explaining the observed changes in HDL-cholesterol and other HDL-related parameters. CONCLUSIONS: In HIV-1 infected patients treated with a regimen of stavudine, didanosine and NVP we found changes in lipids and lipoproteins which are associated with a sharp decrease in risk for CAD in other settings. If confirmed in larger studies, these findings both may influence the initial choice of therapy for HIV-1 infection, and might lead to novel approaches targeted at raising HDL-cholesterol for CAD prevention.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Doença da Artéria Coronariana/prevenção & controle , Infecções por HIV/tratamento farmacológico , Lipídeos/sangue , Nevirapina/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Quimioterapia Combinada , Feminino , Infecções por HIV/sangue , HIV-1 , Humanos , Lipoproteínas/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To evaluate the safety and antiviral activity of different dose levels of the HIV protease inhibitor ABT-378 combined with low-dose ritonavir, plus stavudine and lamivudine in antiretroviral-naive individuals. DESIGN: Prospective, randomized, double-blind, multicenter. METHODS: Eligible patients with plasma HIV-1 RNA > 5000 copies/ml received ABT-378 200 or 400 mg with ritonavir 100 mg every 12 h; after 3 weeks stavudine 40 mg and lamivudine 150 mg every 12 h were added (group I, n = 32). A second group initiated treatment with ABT-378 400 mg and ritonavir 100 or 200 mg plus stavudine and lamivudine every 12 h (group II, n = 68). RESULTS: Mean baseline HIV-1 RNA was 4.9 log10 copies/ml in both groups and CD4 cell count was 398 x 10(6)/l and 310 x 10(6)/l in Groups I and II respectively. In the intent-to-treat (ITT; missing value = failure) analysis at 48 weeks, HIV-1 RNA was < 400 copies/ml for 91% (< 50 copies/ml, 75%) and 82% (< 50 copies/ml, 79%) of patients in groups I and II respectively. Mean steady-state ABT-378 trough concentrations exceeded the wild-type HIV-1 EC50 (effective concentration to inhibit 50%) by 50-100-fold. The most common adverse events were abnormal stools, diarrhea and nausea. No patient discontinued before 48 weeks because of treatment-related toxicity or virologic rebound. CONCLUSIONS: ABT-378 is a potent, well-tolerated protease inhibitor. The activity and durable suppression of HIV-1 observed in this study is probably attributable to the observed tolerability profile and the achievement of high ABT-378 plasma concentrations.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Lamivudina/uso terapêutico , Pirimidinonas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/uso terapêutico , Estavudina/uso terapêutico , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Contagem de Linfócito CD4 , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , Infecções por HIV/fisiopatologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/farmacocinética , Humanos , Lamivudina/efeitos adversos , Lamivudina/farmacocinética , Lopinavir , Masculino , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética , RNA Viral/sangue , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/farmacocinética , Ritonavir/efeitos adversos , Ritonavir/farmacocinética , Estavudina/efeitos adversos , Estavudina/farmacocinética , Carga ViralRESUMO
OBJECTIVE: To compare the virologic activity of continued lamivudine (3TC) versus a switch to delavirdine (DLV) when initiating protease inhibitor therapy in nucleoside-experienced patients. DESIGN: Randomized, open-label, multi-center study. SETTING: Adult AIDS clinical trials units. PATIENTS: Protease and non-nucleoside reverse transcriptase inhibitor-naive patients who had received 3TC plus zidovudine (ZDV), stavudine (d4T), or didanosine (ddl) for at least 24 weeks. INTERVENTIONS: Patients with plasma HIV-1 RNA levels > 500 copies/ml who previously received d4T + 3TC or ddI + 3TC were randomized to ZDV + 3TC + indinavir (IDV) or ZDV + DLV + IDV. MAIN OUTCOME MEASURES: Primary endpoints were the proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at 24 weeks, and occurrence of serious adverse events. The proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at week 48 was a secondary endpoint. RESULTS: At week 24, 58% of subjects in the ZDV + 3TC + IDV arm and 73% in the ZDV + DLV + IDV arm had plasma HIV-1 RNA levels < or = 200 copies/ml (P = 0.29). At week 48, plasma HIV-1 RNA levels were < or = 200 copies/ml in 48% and 83%, respectively (P = 0.007). Rash and hyperbilirubinemia occurred more frequently in the DLV arm than in the 3TC arm. Steady-state plasma IDV levels were higher among patients in the DLV arm as compared with the 3TC arm. CONCLUSIONS: Substituting DLV for 3TC when adding IDV improved virologic outcome in nucleoside-experienced patients. This result might be explained, in part, by the positive effect of DLV on IDV pharmacokinetics.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Delavirdina/uso terapêutico , Inibidores da Protease de HIV/uso terapêutico , Indinavir/uso terapêutico , Lamivudina/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Estavudina/uso terapêutico , Zidovudina/uso terapêutico , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Adulto , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Feminino , Inibidores da Protease de HIV/sangue , Humanos , Indinavir/sangue , Masculino , Fatores de Tempo , Carga ViralRESUMO
OBJECTIVE: To study the antiviral activity of lamivudine (3TC) plus zidovudine (ZDV), didanosine (ddl), or stavudine (d4T). DESIGN: Randomized, placebo-controlled, partially double-blinded multicenter study. SETTING: Adult AIDS Clinical Trials Units. PATIENTS: Treatment-naive HIV-infected adults with 200-600x10(6) CD4 T lymphocytes/l. INTERVENTIONS: Patients were openly randomized to a d4T or a ddl limb, then randomized in a blinded manner to receive: d4T (80 mg/day), d4T plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos; or ddl (400 mg/day), ddl plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos. After 24 weeks 3TC was added for patients assigned to the monotherapy arms. MAIN OUTCOME MEASURE: The reduction in plasma HIV-1 RNA level at weeks 24 and 48. RESULTS: Two hundred ninety-nine patients were enrolled. After 24 weeks the mean reduction in plasma HIV-1 RNA copies/ml from baseline was 0.49 log10 (d4T monotherapy) versus 1.03 log10 (d4T plus 3TC; P = 0.001), and 0.68 log10 (ddl monotherapy) versus 0.82 log10 (ddl plus 3TC; P>0.22). After 48 weeks the mean reduction was 1.08 log10 (d4T plus 3TC) versus 1.01 log10 (ZDV plus 3TC) in the d4T limb (P = 0.66), and 0.94 log10 (ddl plus 3TC) versus 0.88 log10 (ZDV plus 3TC; P = 0.70) in the ddl limb. CONCLUSIONS: 3TC added significantly to the virologic effects of d4T, but not ddl, in treatment-naive patients. 3TC plus d4T produced virologic changes comparable to those of 3TC plus ZDV. These results support the use of 3TC with either ZDV or d4 as a component of initial combination antiretroviral therapy.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Lamivudina/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Didanosina/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , HIV-1/fisiologia , Humanos , Masculino , RNA Viral/sangue , Estavudina/uso terapêutico , Carga Viral , Zidovudina/uso terapêuticoRESUMO
Fifty-eight AIDS patients who previously had Pneumocystis carinii pneumonia (PCP) were enrolled in an open trial of zidovudine therapy. We analyzed baseline clinical and laboratory parameters to identify predictors of outcome. Fifty-eight patients were followed for a mean of 26.5 weeks. There were 17 deaths; the probability of survival at 24 weeks was 0.81. Forty-one participants had unsuccessful outcomes, which included new opportunistic infections (24), progressive neurologic deterioration (2), and drug toxicity, excluding anemia, necessitating discontinuation of zidovudine (15). Only 24 subjects (41%) were receiving zidovudine at the end of the study period including 17 who had neither opportunistic infection nor toxicity. Low baseline hemoglobin level (p less than 0.001) and poor performance status as measured by the Karnofsky scale (p less than 0.01) independently predicted unsuccessful outcome and early death. Low hemoglobin (p = 0.001), low platelet count (p = 0.016), and increased time since PCP (p = 0.008) predicted development of drug toxicity. Neither CD4 lymphocyte count nor p24 antigenemia correlated with outcome.