RESUMO
Surgical site occurrences (SSOs) affect up to or over 25% of patients undergoing operative procedures, with the subset of surgical site infections (SSIs) being the most common. Commercially available closed incision negative pressure therapy (ciNPT) may offer surgeons an additional option to manage clean, closed surgical incisions. We conducted an extensive literature search for studies describing ciNPT use and assembled a diverse panel of experts to create consensus recommendations for when using ciNPT may be appropriate. A literature search of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials using key words 'prevention', 'negative pressure wound therapy (NPWT)', 'active incisional management', 'incisional vacuum therapy', 'incisional NPWT', 'incisional wound VAC', 'closed incisional NPWT', 'wound infection', and 'SSIs' identified peer-reviewed studies published from 2000 to 2015. During a multidisciplinary consensus meeting, the 12 experts reviewed the literature, presented their own ciNPT experiences, identified risk factors for SSOs and developed comprehensive consensus recommendations. A total of 100 publications satisfied the search requirements for ciNPT use. A majority presented data supporting ciNPT use. Numerous publications reported SSI risk factors, with the most common including obesity (body mass index ≥30 kg/m2 ); diabetes mellitus; tobacco use; or prolonged surgical time. We recommend that the surgeon assess the individual patient's risk factors and surgical risks. Surgeons should consider using ciNPT for patients at high risk for developing SSOs or who are undergoing a high-risk procedure or a procedure that would have highly morbid consequences if an SSI occurred.
Assuntos
Anti-Infecciosos/uso terapêutico , Tratamento de Ferimentos com Pressão Negativa/métodos , Tratamento de Ferimentos com Pressão Negativa/normas , Guias de Prática Clínica como Assunto , Infecção da Ferida Cirúrgica/tratamento farmacológico , Infecção da Ferida Cirúrgica/microbiologia , Ferida Cirúrgica/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Consenso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: Risk of subsequent diagnosis of HIV in persons diagnosed with newly acquired syphilis, and syphilis in HIV-infected persons, are of interest as these infections are markers of unsafe sex. METHODS: From a nationwide register, all Danish men aged >16 years diagnosed with syphilis in the period 2000-2010 (n=1217) were identified, and subsequently data on HIV status was extracted from the Danish HIV Cohort Study. We used Kaplan-Meier analysis to estimate the 5-year risk of HIV and second syphilis infection, and Cox regression to determine incidence rate ratios (IRR). RESULTS: The 5-year risk of HIV diagnosis was 9.8% (95% CI 7.0% to 12.6%). Those with a second diagnosis of syphilis had a higher risk of being diagnosed with HIV (IRR=3.1, 95% CI 1.2 to 8.0). The 5-year risk for a second diagnosis of syphilis was 14.8% (95% CI 12.1% to 17.4%) and HIV-infected persons had a higher risk of a second syphilis diagnosis (IRR=4.0, 95% CI 2.8 to 5.9). Sixty-five percent of the persons were men having sex with men (MSM). Thirty-four percent of the HIV-infected persons had viral load >1000 copies/ml at time of syphilis diagnosis. CONCLUSIONS: The substantial risks of syphilis and HIV infection in men diagnosed with one of these sexually transmitted diseases indicate a high frequency of unsafe sex in the Danish MSM population. As one-third of the HIV-infected persons diagnosed with syphilis had high viral loads, our data support initiation of antiretroviral therapy in all HIV-infected MSM to reduce HIV transmission.
Assuntos
Infecções por HIV/epidemiologia , Comportamento Sexual/estatística & dados numéricos , Sífilis/diagnóstico , Sexo sem Proteção/prevenção & controle , Adolescente , Adulto , Contagem de Linfócito CD4 , Dinamarca/epidemiologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Sistema de Registros , Fatores de Risco , Comportamento de Redução do Risco , Vigilância de Evento Sentinela , Sífilis/epidemiologia , Sífilis/prevenção & controle , Sexo sem Proteção/estatística & dados numéricos , Carga ViralRESUMO
BACKGROUND: In HIV-1-infected individuals, levels of CD4+ T lymphocytes are depleted and regulatory T-lymphocytes (Tregs) are elevated. In vitro studies have demonstrated effects of vitamin D on the growth and differentiation of these cells. We speculated whether supplementation with vitamin D could have an effect on CD4+ T lymphocytes or Tregs in HIV-1-infected males. METHODS: We conducted a placebo-controlled randomized study that ran for 16 weeks and included 61 HIV-1-infected males, of whom 51 completed the protocol. The participants were randomized to 1 of 3 daily treatments: (1) 0.5-1.0 µg calcitriol and 1200 IU (30 µg) cholecalciferol, (2) 1200 IU cholecalciferol, (3) placebo. Percentages of the following T-lymphocyte subsets were determined: naïve CD4+ and CD8+ cells, activated CD4+ and CD8+ cells, and CD3+CD4+CD25+CD127low Tregs. Furthermore 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, and parathyroid hormone were measured. RESULTS: No significant changes of the studied T-lymphocyte subsets occurred in the treatment groups compared to the placebo group. Increases in 1,25-dihydroxyvitamin D were associated with increases in activated CD4+ T lymphocytes (P = .001) and Tregs (P = .01) in adjusted models. Changes in parathyroid hormone correlated inversely with Tregs (P = .02). Smokers had higher levels of naïve CD4+ T lymphocytes (37% vs 25%;P = .01), naïve CD8+ T lymphocytes (28% vs 19%; P = .03), and Tregs (9% vs 7%; P = .03). CONCLUSION: Cholecalciferol and calcitriol administered during 16 weeks did not change the levels of T-lymphocyte fractions compared to placebo. However, increases in 1,25-dihydroxyvitamin D were associated with an expansion of activated CD4+ cells and Tregs.
Assuntos
Síndrome da Imunodeficiência Adquirida/imunologia , Linfócitos T CD4-Positivos/imunologia , HIV-1 , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico , Síndrome da Imunodeficiência Adquirida/sangue , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Adulto , Terapia Antirretroviral de Alta Atividade , Método Duplo-Cego , Humanos , Modelos Lineares , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Linfócitos T Reguladores/imunologia , Vitamina D/sangueRESUMO
To increase the understanding of mechanisms of HIV control we have genetically and immunologically characterized a full-length HIV-1 isolated from an acute infection in a rare case of undetectable viremia. The subject, a 43-year-old Danish white male (DK1), was diagnosed with acute HIV-1 infection after 1 year in Uganda. Following transient antiretroviral therapy DK1 maintained undetectable viral load for more than 10 years. His Ugandan wife (UG1) developed high viral load. HIV-1 sequences from both individuals were compared by bootscanning for recombination break points. Diversity plots and phylogenic trees were constructed and diversity and evolutionary distances were calculated. Intracellular IFN-gamma in CD8(+)CD3(+) T-lymphocyte reactions was investigated by intracellular flow cytometry (IC-FACS). Virus isolates from both patients were A1D intersubtype recombinants showing 98% sequence homology in shared regions. Four of seven crossover points were identical; however, the env gene from UG1 was subtype D, but A1 in DK1. Both viruses encoded proteins of the expected length and replicated equally well in vitro. DK1 and UG1 shared the HLA-A02 tissue type. HLA-A02-restricted CD8(+) T cell IFN-gamma IC-FACS response in DK1 was detected against only one (Pol(476)) of 23 conserved epitopes. Neutralizing antibodies were induced only to the homologous isolate. These results indicate an A1D intersubtype recombination or transmission of a minor variant. Transient early antiretroviral therapy may have induced full HIV-1 control in this individual mediated by a narrow specific cytotoxic T lymphocyte and neutralizing antibody response and/or other factors yet to be characterized.
Assuntos
Genoma Viral , Infecções por HIV/virologia , HIV-1/genética , HIV-1/imunologia , RNA Viral/genética , Recombinação Genética , Adulto , Anticorpos Antivirais/sangue , Complexo CD3/análise , Linfócitos T CD8-Positivos/química , Linfócitos T CD8-Positivos/imunologia , Análise por Conglomerados , Dinamarca , Epitopos de Linfócito T/imunologia , Saúde da Família , Feminino , Genótipo , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Humanos , Interferon gama/análise , Masculino , Dados de Sequência Molecular , Testes de Neutralização , Filogenia , Análise de Sequência de DNA , Homologia de Sequência , Sorotipagem , UgandaRESUMO
OBJECTIVE: To compare the outcome of highly active antiretroviral therapy (HAART) in HIV-infected patients initiating equivalent regimens within and outside a randomized controlled trial (RCT). STUDY DESIGN AND SETTING: The Danish Protease Inhibitor Study (DAPIS) was a national multicenter RCT comparing initial treatment with indinavir, ritonavir, or saquinavir/ritonavir during 96 weeks. From the Danish HIV Cohort Study we identified all patients initiating one of these protease-inhibitor-based HAART regimens: 425 patients within DAPIS and 677 outside the trial. We compared viral load, CD4 count response, and mortality. RESULTS: At weeks 96 and 240, trial participants were more likely than nonparticipants to have undetectable viral load (adjusted odds ratio [adOR] 1.28 [95% CI=0.94-1.74] and 1.70 [95% CI=1.16-2.50]) and a CD4 increase > or =100 cells/microl (adOR 1.37 [95% CI=1.03-1.82] and 1.53 [95% CI=1.04-2.25]). For antiretroviral-experienced, but not for antiretroviral-naïve patients, trial participants had a lower risk of death (mortality rate ratio [MRR]=0.46 [95% CI=0.27-0.77]) than nonparticipants. This effect was moderated in adjusted analyses (MRR=0.60 [0.33-1.07]). CONCLUSIONS: Compared to nontrial patients, trial participants had better response to HAART. The differences were small defying the notion that results obtained in RCTs are unachievable in routine clinical practice.
Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto , Contagem de Linfócito CD4 , Fatores de Confusão Epidemiológicos , Métodos Epidemiológicos , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND: Initiation of antiretroviral therapy during primary human immunodeficiency virus (HIV)-1 infection may confer long-term benefit. METHODS: After initiation of zidovudine, lamivudine, abacavir, and amprenavir therapy in patients in the QUEST cohort, predictors of virological outcome, virological and immunological changes, and adverse events were evaluated over 48 weeks. RESULTS: One hundred forty-eight patients started antiretroviral therapy during primary HIV-1 infection with < or =3 bands on Western Blot (median plasma HIV-1 RNA load, 5.4 log copies/mL; median CD4 cell count, 517 cells/mm(3)). By week 48, 36% of patients had stopped treatment or were lost to follow-up. Among the 115 patients receiving follow-up care at week 48 (102 of whom were receiving antiretroviral therapy), the median viral load decrease was -5.4 log copies/mL (interquartile range [IQR], -6.4 to -3.9 log copies/mL), and the median increase in CD4 cell count was 147 cells/mm(3) (IQR, -1 to 283 cells/mm(3)); 84.2% of patients had a viral load < or =50 copies/mL, and 44.7% of patients had a viral load < or =3 copies/mL. The median cell-associated RNA level decreased from 3.4 log copies/million PBMCs (IQR, 2.9-4.1 log copies/million PBMCs) to 0.8 log copies/million PBMCs (IQR, 0.5-1.4 log copies/million PBMCs), and the median cell-associated DNA level decreased from 2.8 log copies/million PBMCs (IQR, 2.4-3.0 log copies/million PBMCs) to 1.6 log copies/million PBMCs (IQR, 1.2-1.9 log copies/million PBMCs); 33.3% of patients had an undetectable RNA level, and 9.5% of patients had an undetectable cell-associated DNA level. The median CD8(+)/CD38(++) T cell count decreased from 459 cells/mm(3) (IQR, 208-974 cells/mm(3)) to 33 cells/mm(3) (IQR, 19-75 cells/mm(3)). Baseline CD8(+)/CD38(++) T cell count and cell-associated DNA level were independent inverse predictors for reaching a viral load < or =3 copies/mL. Eighty-three patients experienced a serious adverse event (median duration of an adverse event, 15 days).Conclusions. Initiation of antiretroviral therapy during primary HIV-1 infection was associated with very significant antiretroviral activity and a decrease in immune activation. Lower baseline CD8(+)/CD38(++) T cell count and cell-associated DNA level were predictive of achieving a viral load < or =3 copies/mL.
Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Adulto , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Estudos de Coortes , Etnicidade , Europa (Continente) , Genótipo , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Carga ViralRESUMO
A fast-track pathway has been established in Denmark to investigate patients with serious nonspecific symptoms and signs of cancer (NSSC), who are not eligible to enter an organ-specific cancer program. The prevalence of cancer in this cohort is approximately 20%. The optimal screening strategy in patients with NSSC remains unknown. The aim of the study was to investigate whether 18F-FDG PET/CT was superior to CT as an initial imaging modality in patients with NSSC. In a randomized prospective trial, the imaging modalities were compared with regard to diagnostic performance. Methods: Two hundred patients were randomized 1:1 to whole-body 18F-FDG PET/CT or CT of the thorax and abdomen as the imaging modality. A tentative diagnosis was established after first-line imaging. The final referral diagnosis was adjudicated by the physician, when sufficient data were available. Results: One hundred ninety-seven patients were available for analysis because 3 patients withdrew consent before scanning. Thirty-nine (20%) patients were diagnosed with cancer, 10 (5%) with an infection, 15 (8%) with an autoimmune disease, and 76 (39%) with other diseases. In the remaining 57 patients (28%), no specific disease was found. 18F-FDG PET/CT had a higher specificity (96% vs. 85%; P = 0.028) and a higher accuracy (94% vs. 82%; P = 0.017) than CT. However, there were no statistically significant differences in sensitivity (83% vs. 70%) or negative predictive values (96% vs. 92%). No difference in days to final referral diagnosis according to randomization group could be shown (7.2 vs. 7.6 d). However, for the subgroups in which the imaging modality showed a suggestion of malignancy, there was a significant delay to final diagnosis in the CT group compared with the 18F-FDG PET/CT group (11.6 vs. 5.7 d; P = 0.02). Conclusion: Compared with CT, we found a higher diagnostic specificity and accuracy of 18F-FDG PET/CT for detecting cancer in patients with NSSC. 18F-FDG PET/CT should therefore be considered as first-line imaging in this group of patients.
Assuntos
Detecção Precoce de Câncer/estatística & dados numéricos , Fluordesoxiglucose F18 , Neoplasias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/estatística & dados numéricos , Tomografia Computadorizada por Raios X/métodos , Imagem Corporal Total/estatística & dados numéricos , Dinamarca/epidemiologia , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Masculino , Neoplasias/epidemiologia , Variações Dependentes do Observador , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Prevalência , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Avaliação de Sintomas , Imagem Corporal Total/métodosRESUMO
BACKGROUND: Lamivudine (3TC) therapy can cause the emergence of M1841/V. Previous studies suggest a higher fidelity of the mutant reverse transcriptase and lower replication capacity of the mutant virus. No data exist from clinical comparative studies evaluating the benefit of M1841/V in patients receiving combination antiretroviral therapy (cART). METHODS: HIV-1-infected adults failing a 3TC-containing regimen were randomized to continue (On-3TC) or discontinue 3TC (Off-3TC) whilst receiving cART. The primary efficacy measure was the log10 average-area-under-the-curve-minus-baseline reduction in HIV RNA over 48 weeks. Cryopreserved plasma samples from patients with baseline and > or =1 follow-up sample with HIV RNA >500 copies/ml were sequenced for a nucleotide distances substudy. Evolutionary distances were compared between treatment arms and between viruses with and without M1841/V. RESULTS: The overall 48-week log10 HIV RNA change was -1.4 (95% CI: -1.6, -1.1) for On-3TC (n=65) and -1.5 (95% CI: -1.7, -1.2) for Off-3TC (n=66; P=0.51). No difference was seen in the magnitude of the CD4+ T-cell count increases (median increase: 87 vs 76 cells/ml for 3TC vs Off-3TC, respectively). Thirty-seven patients had baseline and follow-up sequencing. Overall, there were 1.2 (95% CI: -2.2, 4.6) more nucleotide substitutions from baseline for Off-3TC patients (P=0.50), and 10.7 (95% CI: 7.5, 14.0) fewer nucleotide changes in viruses containing M18411V (P<0.0001). CONCLUSION: This study found no added virological or immunological benefit of continuing 3TC in patients on cART harbouring M1841/V. Evolutionary distances from baseline were larger in viruses that did not contain M1841/V. More discernable benefits may be seen in patients with fewer drug options as potent cART may eclipse a benefit of M1841/V in COLATE.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Lamivudina/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Lamivudina/uso terapêutico , Masculino , Mutação , RNA Viral/sangue , Inibidores da Transcriptase Reversa/uso terapêutico , Falha de Tratamento , Resultado do TratamentoRESUMO
BACKGROUND: Although tuberculosis (TB) is a minor problem in Denmark, severe and complicated cases occur in HIV positive. Since the new M. tuberculosis specific test for latent TB, the QuantiFERON-TB In-Tube test (QFT-IT) became available the patients in our clinic have been screened for the presence of latent TB using the QFT-IT test. We here report the results from the first patients screened. METHODS: On a routine basis the QFT-IT test was performed and the results from 590 HIV positive individuals consecutively tested are presented here. CD4 cell count and TB risk-factors were recorded from patient files. MAIN FINDINGS: 27/590(4.6%) of the individuals were QFT-IT test positive, indicating the presence of latent TB infection. Among QFT-IT positive patients, 78% had risk factors such as long-term residency in a TB high endemic area (OR:5.7), known TB exposure (OR:4.9) or previous TB disease (OR:4.9). The prevalence of latent TB in these groups were 13%, 16% and 19% respectively. There was a strong correlation between low CD4 T-cell count and a low mitogen response (P < 0.001;Spearman) and more patients with low CD4 cell count had indeterminate results. CONCLUSION: We found an overall prevalence of latent TB infection of 4.6% among the HIV positive individuals and a much higher prevalence of latent infection among those with a history of exposure (16%) and long term residency in a high endemic country (13%). The QFT-IT test may indeed be a useful test for HIV positive individuals, but in severely immunocompromised, the test may be impaired by T-cell anergy.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Interferon gama/sangue , Mycobacterium tuberculosis/fisiologia , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/sangue , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Adulto , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/química , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/microbiologia , Dinamarca/epidemiologia , Testes Diagnósticos de Rotina/métodos , Feminino , HIV , Infecções por HIV/complicações , Humanos , Interferon gama/análise , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/etiologiaRESUMO
BACKGROUND: Highly active antiretroviral therapy containing three nucleoside reverse transcriptase inhibitors has been somewhat successful, but the clinical efficacy is unclear. METHODS: Randomized, controlled, open-label trial of 180 antiretroviral drug-naive HIV-infected patients allocated to a regimen of abacavir, stavudine and didanosine (A/S/D, n = 60), ritonavir and saquinavir (R/S 400/400 mg twice daily; n = 60) or nelfinavir and nevirapine (N/N 1250/200 mg twice daily; n = 60); the latter two in combination with lamivudine and zidovudine. The primary endpoint was HIV plasma RNA < or = 20 copies/ml after 48 weeks. RESULTS: At baseline, the median CD4 cell count was 161 x 106 cells/l (range, 0-920) and the HIV RNA was 5.0 log10 copies/ml (range, 2.7-6.7). At 48 weeks, 43% in the A/S/D arm had a HIV RNA < or = 20 copies/ml, compared with 69% in the N/N arm (P < 0.01) and 62% in the R/S arm (P < 0.05). In a multivariate analysis, the A/S/D arm had an odds ratio of obtaining a viral load of < or = 20 copies/ml at week 48 of 0.25 [95% confidence interval (CI) 0.10-0.59] versus N/N and 0.53 (95% CI, 0.33-0.83) versus R/S. The A/S/D arm had a particularly poor outcome in patients with higher viral load and AIDS at baseline: 63% had to discontinue A/S/D (any drug). Side effects were more frequent in the A/S/D arm and included neuropathy 27%, suspicion of hypersensitivity 12%, and increase in lactate accompanied by systemic symptoms 8%. CONCLUSION: The A/S/D regimen had a low efficacy and a high frequency of adverse events and cannot be recommended.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Didanosina/administração & dosagem , Didesoxinucleosídeos/administração & dosagem , Estavudina/administração & dosagem , Adulto , Idoso , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Contagem de Linfócito CD4/métodos , Didanosina/efeitos adversos , Didesoxinucleosídeos/efeitos adversos , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Lactatos/sangue , Masculino , Pessoa de Meia-Idade , Nelfinavir/administração & dosagem , Nelfinavir/efeitos adversos , Doenças do Sistema Nervoso/induzido quimicamente , Nevirapina/administração & dosagem , Nevirapina/efeitos adversos , RNA Viral/análise , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Saquinavir/administração & dosagem , Saquinavir/efeitos adversos , Estavudina/efeitos adversos , Resultado do TratamentoRESUMO
Antiretroviral treatment with three nucleoside reverse transcriptase inhibitors (NRTIs) is widely used, but the combination of abacavir, didanosine and stavudine has never been investigated. We describe the surprising and consistent genotypic and phenotypic outcome in patients failing this combination. As part of a Danish multicentre study, 60 antiretroviral-naive patients were randomized to treatment with abacavir, didanosine and stavudine. Failure was defined as one HIV-1 RNA >400 copies/ml. Genotyping was performed using TrueGene HIV-1 assay (Visible Genetics, London, UK). Phenotypic susceptibilities were determined with the Virco Antivirogram assay. Eight patients failed treatment with a median viral load of 2.980 copies/ml (range 478-5.950). At baseline, five patients were wild-type. Three patients harboured nucleoside excision mutations (NEMs), but phenotypic susceptibilities were within normal range. All five patients with wild-type virus developed K65R and four of these patients also acquired the S68G mutation. Phenotypic susceptibility decreased towards abacavir (median 8.9-fold) and didanosine (median 3.2-fold), while susceptibility towards stavudine was unchanged (median 0.8-fold). Susceptibility towards lamivudine and tenofovir decreased median 14.2- and 4.0-fold, respectively. In two patients with baseline resistance mutations, further accumulation of NEMs and V75T or L74V was observed. One patient developed Q151M. Failure of a triple NRTI regimen is possible and frequent with only the K65R mutation. Under adequate selection pressure K65R can easily emerge in vivo and may compromise several future treatment options including newer NRTIs. The unexpected high incidence of S68G suggests a functional role of this mutation in viruses harbouring K65R.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Didanosina/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Inibidores da Transcriptase Reversa/uso terapêutico , Estavudina/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Dinamarca , Farmacorresistência Viral Múltipla/genética , Genoma Viral , Genótipo , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , Humanos , Dados de Sequência Molecular , Mutação/fisiologia , Fenótipo , Terapia de Salvação , Fatores de Tempo , Falha de TratamentoRESUMO
BACKGROUND: A triple-class HAART regimen may be associated with a better virological effect than conventional regimens, but may also lead to toxicity and more profound resistance. METHODS: Randomized, controlled, open-label trial of 233 protease inhibitor- and non-nucleoside reverse transcriptase inhibitor-naive HIV-infected patients allocated to a regimen of nelfinavir and nevirapine (1250/200 mg twice daily; n = 118) or ritonavir and saquinavir (400/400 mg twice daily; n = 115), both in combination with two nucleoside reverse transcriptase inhibitors. The primary end-point was HIV RNA < or = 20 copies/ml after 48 weeks (missing value = failure). Patients remained under follow-up also in case of switch from the randomized therapy. RESULTS: At baseline, the median CD4 cell counts were 126 (range: 0-942) (nelfinavir/nevirapine) and 150 (0-642) (ritonavir/saquinavir) cells/mm3, and HIV RNA measurements 5.0 copies/ml (1.3-6.4) in both groups. A total of 102 (86%) and 101 (88%) were antiretroviral-naive. 44% discontinued randomized therapy; P = 0.13. Of these, 80 and 73% switched therapy due to adverse events; P = 0.99. At week 48, 69 and 56%, respectively, had a HIV RNA < or = 20 copies/ml; P = 0.037. CONCLUSION: A regimen of nelfinavir/nevirapine had a favourable virological effect and tolerability over a 48-week period compared with ritonavir/saquinavir, when administered in combination with two nucleoside reverse transcriptase inhibitors. However, more extensive follow-up is required to determine the long-term consequences of triple class HAART regimens, including the development of broad drug resistance.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Idoso , Fármacos Anti-HIV/efeitos adversos , Contagem de Linfócito CD4 , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Nelfinavir/administração & dosagem , Nevirapina/administração & dosagem , RNA Viral/sangue , Ritonavir/administração & dosagem , Saquinavir/administração & dosagemRESUMO
BACKGROUND: To assess the impact on virological outcomes of a switch from branded single-tablet regimen (STR) including tenofovir, efavirenz, and emtricitabine (STR-TEE) to generic triple-tablet regimen (TTR), including tenofovir, efavirenz, and lamivudine (TTR-TEL), which was implemented on April 1, 2011 to obtain economic savings. METHODS AND FINDINGS: From the Capital Region of Denmark (covering two-thirds of the Danish HIV patients), we included combination antiretroviral therapy (cART)-naive patients who administered STR-TEE from April 1, 2010 to March 31, 2011 (n = 111) or TTR-TEL from April 1, 2011 to March 31, 2012 (n = 56) and cART-experienced HIV patients who were on STR-TEE from April 1, 2010 (n = 356) or were switched from STR-TEE to TTR-TEL after April 1, 2011 (n = 512). We estimated the fraction with detectable HIV-RNA, development of the 184V/I resistance mutations, and time to switch of cART. Approximately 96.2% of cART-experienced patients on STR-TEE were shifted to TTR-TEL after April 1, 2011. For the naive STR-TEE and TTR-TEL patients, the fractions with detectable HIV-RNA at week 48 were 7.0% and 8.3% and for the cART experienced 4.0% and 4.4%, respectively. The 184V/I resistance mutation was detected in 1 cART-experienced patient on TTR-TEL with virological failure. The risk of switch to a new cART regimen was slightly increased in the cART-experienced population (difference in 1-year risk: 1.5%; 95% confidence interval: -2.4% to 5.4%). CONCLUSIONS: In settings comparable with the Danish health care system, the estimated economic savings from a switch from STR-TEE to TTR-TEL can be realized with negligible short-term risk of adverse outcomes.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Adulto , Fármacos Anti-HIV/economia , Contagem de Linfócito CD4 , Dinamarca/epidemiologia , Esquema de Medicação , Combinação de Medicamentos , Feminino , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Carga ViralRESUMO
Highly active antiretroviral treatment is compromised by viral resistance mutations. Transmitted drug resistance (TDR) is therefore monitored closely, but follow-up studies of these patients are limited. Virus from 1405 individuals diagnosed with HIV-1 in Denmark between 2001 and 2009 was analyzed for TDR, and molecular-epidemiological links and progression of the infection were described based on data from standardized questionnaires, the prospective Danish HIV Cohort Study, and by phylogenetic analysis. Eighty-five individuals were found to be infected with virus harboring mutations resulting in a prevalence of 6.1%, with no changes over time. The main resistance mutations were nucleoside reverse transcriptase inhibitor (NRTI) mutation 215 revertants, as well as nonnucleoside reverse transcriptase inhibitor (NNRTI) mutation 103N/S and protease inhibitor (PI) mutations 90M and 85V. Phylogenetic analysis confirmed 12 transmission chains involving 37 TDR individuals. Of these 21 were also documented epidemiologically. The virus included in the transmission chain carried similar resistance mutations to the TDR index case, whereas controls chains from index cases without TDR were generally without resistance mutations. We observed no difference in progression of the infection between individuals infected with TDR and individuals infected with wild-type HIV-1. The prevalence of TDR is low in Denmark and transmission of dual-drug-resistant HIV-1 is infrequent. The TDR isolates were shown to originate from local patients failing therapy.
Assuntos
Farmacorresistência Viral/genética , HIV-1/efeitos dos fármacos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade , Dinamarca , Feminino , HIV-1/classificação , HIV-1/genética , Humanos , Masculino , Mutação , Filogenia , PrognósticoAssuntos
Infecção Hospitalar/microbiologia , Doença dos Legionários/epidemiologia , Pneumonia Bacteriana/microbiologia , Adulto , Idoso , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/microbiologia , Infecções Comunitárias Adquiridas/transmissão , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/transmissão , Dinamarca/epidemiologia , Feminino , Humanos , Legionella pneumophila/imunologia , Legionella pneumophila/isolamento & purificação , Doença dos Legionários/transmissão , Masculino , Pessoa de Meia-Idade , Pneumonia Bacteriana/epidemiologia , Pneumonia Bacteriana/transmissãoRESUMO
OBJECTIVES: To assess the effect of human immunodeficiency virus (HIV)-1 and syphilis coinfection on HIV-ribonucleic acid (RNA) viral load, CD4 cell count, and the response in rapid plasmin reagin (RPR) to treatment of the syphilis infection. STUDY DESIGN: Cases of syphilis diagnosed during 1 year in HIV-infected patients in Copenhagen were included. HIV-RNA, CD4 cell counts, and RPR-serology were measured before, during, and after syphilis. RESULTS: Forty-one patients were included. CD4 cell count decreased significantly during infection in patients with primary and secondary stages of syphilis (mean 106 cells/mm, P = 0.03). Treatment of syphilis was associated with an increase in the CD4 cell count and a decrease in HIV-RNA in the overall group (mean 66 cells/mm and -0.261 RNA log10 copies/ml, P = 0.02 and 0.04). The serological response rates for 15 patients treated with penicillin and 25 treated with doxycycline were the same. CONCLUSION: Syphilis was associated with a decrease in CD4 cell counts and an increase in HIV-RNA levels that both improved after treatment of syphilis.
Assuntos
Antibacterianos/uso terapêutico , Infecções por HIV/complicações , Sífilis/complicações , Sífilis/tratamento farmacológico , Carga Viral , Adulto , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Dinamarca/epidemiologia , Doxiciclina/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Penicilinas/uso terapêutico , RNA Viral/sangue , Reaginas/sangue , Sífilis/epidemiologia , Sífilis/microbiologia , Resultado do TratamentoRESUMO
BACKGROUND: The majority of chemotherapeutic agents are administered at fixed doses that are close to those maximally tolerated. MATERIAL AND METHODS: This review is based on current knowledge about the metabolism of thiopurines and the clinical implications of genetic polymorphism in thiopurine-S-methyltransferase (TPMT). RESULTS: Intracellularly thiopurines, e.g. 6-MP, are anabolized to cytotoxic 6-thioguanine nucleotides (6-TGN) that are incorporated into DNA and RNA. A competing pathway is S-methylation of 6-MP and its initial nucleotide metabolites by TPMT. In childhood acute lymphocytic leukaemia, high erythrocyte concentrations of 6-TGN correlate with the degree of leukopenia and a good prognosis, while low concentrations appear to be associated with higher risk of relapse. In most populations studied, approximately 10% have intermediate TPMT activity and 1/300 lacks TPMT activity due to one or two mutant TPMT alleles, respectively. INTERPRETATION: Phenotyping or genotyping may be used to identify patients as deficient or intermediate thiopurine metabolizers. This suggests that they should receive a profound or moderate reduction in dosage to avoid haematopoietic toxicity.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Órgãos , Farmacogenética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Purinas/administração & dosagem , Adulto , Antimetabólitos/metabolismo , Antimetabólitos Antineoplásicos/metabolismo , Criança , Genótipo , Humanos , Imunossupressores/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , Fenótipo , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Purinas/metabolismoRESUMO
Current antiretroviral therapy can induce considerable, sustained viral suppression followed by immunological recovery, in which naive CD4 + cells are important. Long-term immunological recovery was investigated during the first 3 y of highly active antiretroviral therapy (HAART) in 210 HIV-1-infected patients. The focus was on the naive CD4 + cell time course and associations between naive CD4 + cell counts and established prognostic markers. Total and naive CD4 + cell counts were measured using flow cytometry. The HIV-RNA detection limit was 20 copies/ml. During 36 months of HAART, the total CD4 + count followed a triphasic pattern, reflecting an initial phase of rapid redistribution from lymphoid tissues, followed by a slow increase, partially due to an increase in naive CD4+ cell count. From Month 18 onwards, both naive and total CD4 + cell counts stabilized, although viral suppression was sustained. There was no association between plasma viral load and the increase in naive CD4 + cell count. Importantly, baseline naive CD4 + cell count was significantly associated with the change in naive CD4 + cell count, suggesting that the naive cell count at baseline does influence the immunological recovery that can be obtained from treatment. Surprisingly, the naive CD4 + cell count tended to stabilize at a subnormal level after 18 months of HAART. This finding merits further investigation.
Assuntos
Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/fisiologia , Adulto , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Subpopulações de Linfócitos T/imunologia , Fatores de TempoAssuntos
Infecções por HIV/transmissão , Soropositividade para HIV/transmissão , Comportamento Sexual , Controle de Doenças Transmissíveis/legislação & jurisprudência , Infecções por HIV/tratamento farmacológico , Soropositividade para HIV/tratamento farmacológico , Heterossexualidade , Humanos , Fatores de Risco , Carga ViralRESUMO
MHC-I-restricted cytotoxic responses are considered a critical component of protective immunity against viruses, including human immunodeficiency virus type 1 (HIV-1). CTLs directed against accessory and early regulatory HIV-1 proteins might be particularly effective; however, CTL epitopes in these proteins are rarely found. Novel artificial neural networks (ANNs) were used to quantitatively predict HLA-A2-binding CTL epitope peptides from publicly available full-length HIV-1 protein sequences. Epitopes were selected based on their novelty, predicted HLA-A2-binding affinity and conservation among HIV-1 strains. HLA-A2 binding was validated experimentally and binders were tested for their ability to induce CTL and IFN-gamma responses. About 69 % were immunogenic in HLA-A2 transgenic mice and 61 % were recognized by CD8(+) T-cells from 17 HLA-A2 HIV-1-positive patients. Thus, 31 novel conserved CTL epitopes were identified in eight HIV-1 proteins, including the first HLA-A2 minimal epitopes ever reported in the accessory and regulatory proteins Vif, Vpu and Rev. Interestingly, intermediate-binding peptides of low or no immunogenicity (i.e. subdominant epitopes) were found to be antigenic and more conserved. Such epitope peptides were anchor-optimized to improve immunogenicity and further increase the number of potential vaccine epitopes. About 67 % of anchor-optimized vaccine epitopes induced immune responses against the corresponding non-immunogenic naturally occurring epitopes. This study demonstrates the potency of ANNs for identifying putative virus CTL epitopes, and the new HIV-1 CTL epitopes identified should have significant implications for HIV-1 vaccine development. As a novel vaccine approach, it is proposed to increase the coverage of HIV variants by including multiple anchor-optimized variants of the more conserved subdominant epitopes.