RESUMO
Mortality of HIV/tuberculosis (TB) patients in Eastern Europe is high. Little is known about their causes of death. This study aimed to assess and compare mortality rates and cause of death in HIV/TB patients across Eastern Europe and Western Europe and Argentina (WEA) in an international cohort study. Mortality rates and causes of death were analysed by time from TB diagnosis (<3 months, 3-12 months or >12 months) in 1078 consecutive HIV/TB patients. Factors associated with TB-related death were examined in multivariate Poisson regression analysis. 347 patients died during 2625 person-years of follow-up. Mortality in Eastern Europe was three- to ninefold higher than in WEA. TB was the main cause of death in Eastern Europe in 80%, 66% and 61% of patients who died <3 months, 3-12 months or >12 months after TB diagnosis, compared to 50%, 0% and 15% in the same time periods in WEA (p<0.0001). In multivariate analysis, follow-up in WEA (incidence rate ratio (IRR) 0.12, 95% CI 0.04-0.35), standard TB-treatment (IRR 0.45, 95% CI 0.20-0.99) and antiretroviral therapy (IRR 0.32, 95% CI 0.14-0.77) were associated with reduced risk of TB-related death. Persistently higher mortality rates were observed in HIV/TB patients in Eastern Europe, and TB was the dominant cause of death at any time during follow-up. This has important implications for HIV/TB programmes aiming to optimise the management of HIV/TB patients and limit TB-associated mortality in this region.
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Coinfecção/mortalidade , Infecções por HIV/mortalidade , Tuberculose/mortalidade , Adulto , Fármacos Anti-HIV/uso terapêutico , Antituberculosos/uso terapêutico , Argentina , Causas de Morte , Estudos de Coortes , Europa (Continente) , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Análise Multivariada , Tuberculose/complicações , Tuberculose/tratamento farmacológicoRESUMO
BACKGROUND: State-of-the-art care involving the utilisation of multiple health care interventions is the basis for an optimal long-term clinical prognosis for HIV-patients. We evaluated health care for HIV patients based on four key indicators. METHODS: Four indicators of health care were assessed: Compliance with current guidelines on initiation of: 1) combination antiretroviral therapy (cART); 2) chemoprophylaxis; 3) frequency of laboratory monitoring; and 4) virological response to cART (proportion of patients with HIV-RNA < 500copies/ml for >90% of time on cART). RESULTS: 7097 EuroSIDA patients were included from Northern (n = 923), Southern (n = 1059), West Central (n = 1290) East Central (n = 1366), Eastern (n = 1964) Europe, and Argentina (n = 495). Patients in Eastern Europe with a CD4 < 200cells/mm(3) were less likely to initiate cART and Pneumocystis jiroveci-chemoprophylaxis compared to patients from all other regions, and less frequently had a laboratory assessment of their disease status. The proportion of patients with virological response was highest in Northern, 89% vs. 84%, 78%, 78%, 61%, 55% in West Central, Southern, East Central Europe, Argentina and Eastern Europe, respectively (p < 0.0001). Compared to Northern, patients from other regions had significantly lower odds of virological response; the difference was most pronounced for Eastern Europe and Argentina (adjusted OR 0.16 [95%CI 0.11-0.23, p < 0.0001]; 0.20[0.14-0.28, p < 0.0001] respectively). CONCLUSIONS: This assessment of HIV health care utilization revealed pronounced regional differences in adherence to guidelines and can help to identify gaps and direct target interventions. It may serve as a tool for the assessment and benchmarking of the clinical management of HIV patients in any setting worldwide.
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Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Pesquisa sobre Serviços de Saúde , Assistência ao Paciente/métodos , Adulto , Argentina/epidemiologia , Benchmarking , Quimioprevenção/métodos , Monitoramento de Medicamentos/métodos , Europa (Continente)/epidemiologia , Feminino , Fidelidade a Diretrizes/estatística & dados numéricos , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Carga ViralRESUMO
BACKGROUND: The HIV epidemic in Russia has increasingly involved reproductive-aged women, which may increase perinatal HIV transmission. METHODS: Standard HIV case-reporting and enhanced perinatal HIV surveillance systems were used for prospective assessment of HIV-infected women giving birth in St. Petersburg, Russia, during 2004-2008. Trends in social, perinatal, and clinical factors influencing mother-to-child HIV transmission stratified by history of injection drug use, and rates of perinatal HIV transmission were assessed using two-sided χ2 or Cochran-Armitage tests. RESULTS: Among HIV-infected women who gave birth, the proportion of women who self-reported ever using injection drugs (IDUs) decreased from 62% in 2004 to 41% in 2008 (P<0.0001). Programmatic improvements led to increased uptake of the following clinical services from 2004 to 2008 (all P<0.01): initiation of antiretroviral prophylaxis at ≤28 weeks gestation (IDUs 44%-54%, non-IDUs 45%-72%), monitoring of immunologic (IDUs 48%-64%, non-IDUs 58%-80%) and virologic status (IDUs 8%-58%, non-IDUs 10%-75%), dual/triple antiretroviral prophylaxis (IDUs 9%-44%, non-IDUs 14%-59%). After initial increase from 5.3% (95% confidence interval [CI] 3.5%-7.8%) in 2004 to 8.5% (CI 6.1%-11.7%) in 2005 (P<0.05), perinatal HIV transmission decreased to 5.3% (CI 3.4%-8.3%) in 2006, and 3.2% (CI 1.7%-5.8%) in 2007 (P for trend<0.05). However, the proportion of women without prenatal care and without HIV testing before labor and delivery remained unchanged. CONCLUSIONS: Reduced proportion of IDUs and improved clinical services among HIV-infected women giving birth were accompanied by decreased perinatal HIV transmission, which can be further reduced by increasing outreach and HIV testing of women before and during pregnancy.
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Infecções por HIV/epidemiologia , Infecções por HIV/transmissão , Transmissão Vertical de Doenças Infecciosas/estatística & dados numéricos , Adulto , Feminino , Humanos , Incidência , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Modelos Estatísticos , Gravidez , Estudos Prospectivos , Fatores de Risco , Federação Russa/epidemiologiaRESUMO
OBJECTIVE: The purpose of this study was to evaluate the effectiveness of a human immunodeficiency virus (HIV) rapid testing (RT) program. STUDY DESIGN: From April 13, 2004, to April 13, 2005, pregnant women at 2 high-risk maternity hospitals with no or incomplete HIV testing results (negative tests at <34 weeks, none thereafter) were offered point-of-care RT, with antiretroviral prophylaxis for RT-positive women and their infants. RESULTS: Overall, 89.2% of eligible women (3671/4117) underwent RT, of whom 90.4% received results before delivery. HIV seroprevalence among all women who underwent RT was 2.7% (100/3671 women); among previously untested women, seroprevalence was 6.5% (90/1375 women); the incidence of HIV seroconversion among women with previous negative tests during pregnancy was 0.4% (10/2296 women). After adjustment, the main predictor of receiving RT results after delivery was late admission. Among HIV-exposed infants, 97.9% (92/94) received prophylaxis; 61.7% (58/94) had available follow-up data, and 8.6% (5/58) met criteria for definitive or presumptive HIV infection. CONCLUSION: The RT program achieved timely detection of HIV-infected women in labor with unknown HIV status and effectively prevented perinatal HIV transmission.
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Infecções por HIV/diagnóstico , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Complicações Infecciosas na Gravidez/diagnóstico , Diagnóstico Pré-Natal , Kit de Reagentes para Diagnóstico/estatística & dados numéricos , Feminino , HIV/genética , HIV/isolamento & purificação , Infecções por HIV/sangue , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Soroprevalência de HIV , Maternidades , Humanos , Serviços de Saúde Materna/estatística & dados numéricos , Avaliação de Resultados em Cuidados de Saúde , Valor Preditivo dos Testes , Gravidez , Complicações Infecciosas na Gravidez/sangue , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/prevenção & controle , Federação Russa/epidemiologiaRESUMO
INTRODUCTION: It is unknown whether the increased risk of toxicities in antiretroviral-naive HIV-infected patients initiating nevirapine-based (NVPc) combination antiretroviral therapy (cART) with high CD4+ T-cell counts is also observed when NVPc is initiated in cARTexperienced patients. PATIENTS AND METHODS: 1,571 EuroSIDA patients started NVPc after 1/1/1999, with CD4+ T-cell counts and viral load measured in the 6 months before starting treatment, and were stratified into four groups based on CD4+ T-cell counts at initiation of NVPc (high [H], > 400/mm3 or > 250/mm3 for male or female, respectively, or low [L], < or = 400/mm3 or 5250/mm3 for male or female) and prior antiretroviral experience (antiretroviral-naive [N] or -experienced [E]). Cox proportional hazards models compared the risks of discontinuation of nevirapine due to toxicities or patient/physician choice (TOXPC). RESULTS: After adjustment, there was a significantly lower risk of discontinuation of nevirapine due to TOXPC in the HE group (n = 588; proportion discontinued by 3/12 months: 10/17%, respectively) than in HN (n = 62; 21/32% respectively; overall relative hazard [RH]: 0.56; 95% confidence interval [CI]: 0.34-0.94; P = 0.027). This difference was most pronounced during the first 3 months of NVPc (RH: 0.44; 95% CI: 0.23-0.87; P = 0.017). There were no deaths in the 6 months after starting NVPc resulting from exposure to < 3 months of NVPc exposure within the HE group (incidence: 0; per 1,000 person-years follow up; 95% CI: 0-6.9). After adjustment, there were no differences between the HE and HN groups in discontinuation due to TOXPC in patients starting efavirenz-based cART (RH: 0.91; 95% CI: 0.60-1.38; P = 0.66) or protease-inhibitor-based cART (RH: 1.13; 95% CI: 0.77-1.66; P = 0.52). CONCLUSIONS: Results from this non-randomized study suggest that NVPc might be safer to initiate in antiretroviral-experienced than in antiretroviral-naive patients with high CD4+ T-cell counts.
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Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Argentina , Contagem de Linfócito CD4 , Doença Hepática Induzida por Substâncias e Drogas , Europa (Continente) , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Nevirapina/efeitos adversos , Nevirapina/uso terapêutico , Modelos de Riscos Proporcionais , Fatores de Risco , Resultado do Tratamento , Suspensão de TratamentoRESUMO
The HIV-1 subtype A epidemic affecting injecting drug users (IDU) in former Soviet Union (FSU) countries started dramatically in Odessa, southern Ukraine, in 1995, and is caused by a variant of monophyletic origin, often designated IDU-A. We phylogenetically analyzed one near full-length genome and two partial sequences of three HIV-1 subtype A viruses collected in St. Petersburg, Russia, heterosexually transmitted in 1992-1994. The sequences branched basally to the IDU-A clade, together with eight viruses from Odessa collected in 1993, all presumably acquired heterosexually, and two viruses from the Democratic Republic of Congo. Of all other FSU sequences in databases, only those from three recently collected viruses, one from Ukraine and two from northwestern Russia, at least one of them acquired heterosexually, branched basally to the IDU-A cluster. The results indicate that the FSU IDU-A variant derives from a strain that initially propagated heterosexually in Ukraine and originated in central Africa.
Assuntos
Genoma Viral , Infecções por HIV/epidemiologia , HIV-1/genética , Sequência de Bases , República Democrática do Congo/epidemiologia , Infecções por HIV/transmissão , Infecções por HIV/virologia , HIV-1/classificação , Humanos , Epidemiologia Molecular , Dados de Sequência Molecular , Filogenia , Federação Russa/epidemiologia , Abuso de Substâncias por Via Intravenosa/virologia , Ucrânia/epidemiologiaRESUMO
In St Petersburg, Russia, a rapid HIV-testing programme was implemented in April 2004 for high-risk women giving birth. Among 670 women without prenatal care who received rapid HIV testing, 6.4% (43) had positive results. Among HIV-positive mothers, receipt of intrapartum antiretroviral prophylaxis increased significantly compared to pre-programme levels (76 versus 41%). Additionally, infant abandonment increased significantly (50% versus 26%), and was 10 times greater in women with unintended versus intended pregnancies (73% versus 7%).
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Sorodiagnóstico da AIDS , Fármacos Anti-HIV/uso terapêutico , Criança Abandonada , Infecções por HIV/diagnóstico , Infecções por HIV/prevenção & controle , Complicações Infecciosas na Gravidez/diagnóstico , Quimioprevenção , Criança Abandonada/estatística & dados numéricos , Feminino , Humanos , Lactente , Transmissão Vertical de Doenças Infecciosas , Gravidez , Complicações Infecciosas na Gravidez/prevenção & controle , Gravidez não Desejada , Avaliação de Programas e Projetos de Saúde , Federação Russa , Fatores de TempoRESUMO
OBJECTIVE: To evaluate antiviral activity, tolerability, safety and pharmacokinetics of treatment with TMC125 (a non-nucleoside reverse transcriptase inhibitor), 900 mg twice daily for 7 days. DESIGN: Randomized, double-blind, placebo-controlled, phase IIA clinical trial. SETTING: Two hospital clinics in Moscow and St Petersburg, Russian Federation. PARTICIPANTS: Nineteen antiretroviral-naive, HIV-1-infected subjects. INTERVENTIONS: Randomization (2:1) was to twice daily treatment with either 900 mg TMC125 or matched placebo as monotherapy for 7 days. MAIN OUTCOME MEASURES: Change in plasma HIV-1 RNA from baseline values (primary); change in CD4 cell counts from baseline, and evaluation of safety, tolerability and pharmacokinetics of TMC125 treatment (secondary). RESULTS: A mean decrease from baseline in plasma HIV-1 RNA of 1.99 log10 copies/ml and 0.06 log10 copies/ml was achieved after 7 days in the TMC125 and placebo groups, respectively (P < 0.001). Plasma viral daily decay rates of 0.33 log10 copies/ml and 0.02 log10 copies/ml were observed in the TMC125 and placebo groups, respectively (P < 0.001). A steady-state plasma concentration of TMC125 was attained within 5 days of treatment with a mean minimum concentration of 246 ng/ml and a mean maximum concentration of 419 ng/ml. The majority of subjects did not report any adverse events. No abnormalities consistent with changes in blood chemistry, haematology, urinalysis, electrocardiograph or vital signs were observed. CONCLUSIONS: TMC125 administered as monotherapy for 7 days yielded a 1.99 log10 copies/ml reduction in HIV-1 RNA in antiretroviral-naive, HIV-1-infected subjects. TMC125 was well tolerated and represents a promising and highly potent, next generation non-nucleoside reverse transcriptase inhibitor candidate.
Assuntos
Infecções por HIV/tratamento farmacológico , HIV-1 , Piridazinas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Método Duplo-Cego , Farmacorresistência Viral , HIV-1/genética , Humanos , Masculino , Mutação , Nitrilas , Piridazinas/efeitos adversos , Piridazinas/farmacocinética , Pirimidinas , RNA Viral/sangue , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/farmacocinética , Resultado do Tratamento , Carga ViralRESUMO
OBJECTIVE: TMC125, a next generation, non-nucleoside reverse transcriptase inhibitor (NNRTI), demonstrated a remarkable decline of plasma HIV-1 RNA during a phase IIa study. We compared the initial rate of decline of plasma HIV-1 RNA achieved by TMC125 monotherapy with that of a triple class, five-drug regimen, containing drugs from all three currently licensed classes (zidovudine, lamivudine, abacavir, indinavir and nevirapine). METHODS: The decline in plasma HIV-1 RNA of 12 HIV-1 infected, antiretroviral (ART) naive patients treated for 1 week with TMC125 monotherapy was compared with that observed in the ERA study (n = 11). The plasma HIV-1 RNA elimination rate constant was calculated based on at least four plasma HIV-1 RNA measurements during the first week of treatment (first-order elimination) and compared using the Student's t test. RESULTS: Median ages were 23 and 38 years for TMC125 and ERA patients, respectively (P = 0.001), median baseline plasma HIV-1 RNA levels were 4.2 and 4.8 log10 copies/ml (P = 0.001) and median baseline CD4 T-cell counts were 458 x 10(6) and 360 x 10(6) cells/l (P = 0.08). The median plasma HIV-1 RNA elimination rate constant was 0.68/day in TMC125 treated patients, and 0.56/day in ERA participants (P = 0.24). The median decline in plasma HIV-1 RNA after 7 days was 1.92 and 1.76 log10 copies (P = 0.77) and the median increase of CD4 T cells was 119 x 10(6) and 60 x 10(6) cells/l, respectively (P = 0.29). CONCLUSION: Monotherapy with TMC125 in ART-naive, HIV-1-infected individuals resulted in a similar rate of decline of plasma HIV-1 RNA during 1 week of therapy as therapy with a five-drug regimen.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , HIV-1 , Piridazinas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Didesoxinucleosídeos/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Infecções por HIV/sangue , Inibidores da Protease de HIV/uso terapêutico , Humanos , Indinavir/uso terapêutico , Lamivudina/uso terapêutico , Masculino , Nevirapina/uso terapêutico , Nitrilas , Pirimidinas , RNA Viral/sangue , Resultado do Tratamento , Zidovudina/uso terapêuticoRESUMO
PURPOSE: To determine the incidence of and risk factors for electrocardiographic (ECG) abnormalities in adults with diphtheria. METHODS: A prospective study was conducted involving 122 adult patients with respiratory tract diphtheria. Diphtheria was confirmed by isolation of a toxin-producing strain of Corynebacterium diphtheriae. Patients had serial clinical evaluations and ECGs for a minimum of 21 days. RESULTS: Cardiac involvement was detected in 25 (28%) of 88 evaluable patients, with a median time from symptom onset to an abnormal ECG of 9 days (range, 4 to 24 days). In a logistic regression analysis, age (odds ratio [OR] = 4.1; 95% confidence interval [CI]: 1.6 to 11.0), shared accommodation (OR = 2.9; 95% CI: 1.0 to 8.6), fever (OR = 4.2; 95% CI: 1.1 to 16.6), and extensive respiratory tract infection with subcutaneous edema (OR = 7.0; 95% CI: 1.2 to 42.2) were independent risk factors for cardiac involvement. CONCLUSION: Cardiac involvement is a common complication of respiratory tract infection with C. diphtheriae, and occurs more often among older patients, those with lower socioeconomic status, and those with severe respiratory tract involvement.
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Difteria/complicações , Cardiopatias/etiologia , Adolescente , Adulto , Idoso , Difteria/fisiopatologia , Eletrocardiografia , Feminino , Cardiopatias/diagnóstico , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Fatores SocioeconômicosRESUMO
INTRODUCTION: EuroSIDA has previously reported a poorer clinical prognosis for HIV-positive individuals in Eastern Europe (EE) as compared with patients from other parts of Europe, not solely explained by differences in patient characteristics. We explored regional variability in self-reported HIV management at individual EuroSIDA clinics, with a goal of identifying opportunities to reduce the apparent inequalities in health. METHODS: A survey (www.chip.dk/eurosida/csurvey) on HIV management was conducted in early 2014 in all currently active EuroSIDA clinics. Responders in EE were compared with clinics in all other EuroSIDA regions combined (non-EE). Characteristics were compared between regions using Fishers exact test. RESULTS: A total of 80/97 clinics responded (82.5%, 12/15 in EE, 68/82 in non-EE). Participating clinics reported seeing a total of 133,532 patients [a median of 1300 per clinic (IQR 700-2399)]. The majority of clinics requested viral load and CD4 measurements at least every six months for patients on as well as off ART (EE 66.7%, non-EE 75%, p=0,72). Significantly fewer EE clinics performed resistance tests before ART as well as upon treatment failure (Figure 1). Half of the EE clinics indicated following WHO guidelines (EE 50%, non-EE 7.4%, p<0.0001), whereas most non-EE clinics followed EACS guidelines (non-EE 76.5%, EE 41.7%, p=0.017). The majority of EE clinics and » non-EE clinics indicated deferral of ART initiation in asymptomatic individuals until CD4 ≤350 cells/mm(3) (Figure 1). There were no significant regional differences in screening haematology, liver or renal function, which the majority of clinics reported to do routinely. However, EE clinics reported screening significantly less for cardiovascular disease (CVD), and only about half screened for tobacco use, alcohol consumption and drug use (Figure 1). Screening for cervical cancer and for anorectal cancer was low in both regions (Figure 1). CONCLUSIONS: We found significant regional variability in self-reported HIV management across Europe, with less resistance testing, screening for CVD and substance use in EE. EE clinics indicated deferral of ART initiation for longer than non-EE clinics. Adherence to international guidelines for cervical cancer screening was poor in both regions. Whether differences in HIV management are reflected in clinical outcomes deserves further investigation.
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OBJECTIVES: The study aimed at describing characteristics and outcome of tuberculous meningitis (TBM) in HIV-positive patients and comparing these parameters with those of extrapulmonary TB (TBEP) and pulmonary TB (TBP). METHODS: Kaplan-Meier estimation and Poisson regression models were used to assess the mortality following TB diagnosis and to evaluate potential prognostic factors for the 3 groups of TB patients separately. RESULTS: A total of 100 patients with TBM, 601 with TBEP, and 371 TBP were included. Patients with TBM had lower CD4 cell counts and only 17.0% received antiretroviral therapy (ART) at TB diagnosis. The cumulative probability of death at 12 months following TB was 51.2% for TBM (95% CI 41.4-61.6%), 12.3% for TBP (8.9-15.7%), and 19.4% for TBEP (16.1-22.6) (P<0.0001; log-rank test). For TBM, factors associated with a poorer prognosis were not being on ART (adjusted incidence rate ratio (aIRR) 4.00 (1.72-9.09), a prior AIDS diagnosis (aIRR=4.82 (2.61-8.92)), and receiving care in Eastern Europe (aIRR=5.41 (2.58-11.34))). CONCLUSIONS: TBM among HIV-positive patients was associated with a high mortality rate, especially for patients from Eastern Europe and patients with advanced HIV-infection, which urgently calls for public health interventions to improve both TB and HIV aspects of patient management.
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Infecções por HIV/patologia , Infecções por HIV/terapia , Tuberculose Meníngea/patologia , Tuberculose Meníngea/terapia , Adulto , Argentina , Contagem de Linfócito CD4 , Europa (Continente) , Feminino , HIV/isolamento & purificação , HIV/patogenicidade , Infecções por HIV/complicações , Infecções por HIV/mortalidade , Infecções por HIV/virologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Fatores de Risco , Resultado do Tratamento , Tuberculose Meníngea/complicações , Tuberculose Meníngea/mortalidade , Tuberculose Meníngea/virologiaRESUMO
BACKGROUND: Differences in access to care and treatment have been reported in Eastern Europe, a region with one of the fastest growing HIV epidemics, compared to the rest of Europe. This analysis aimed to establish whether there are regional differences in the mortality rate of HIV-positive individuals across Europe, and Argentina. METHODS: 13,310 individuals under follow-up were included in the analysis. Poisson regression investigated factors associated with the risk of death. FINDINGS: During 82,212 person years of follow-up (PYFU) 1,147 individuals died (mortality rate 14.0 per 1,000 PYFU (95% confidence interval [CI] 13.1-14.8). Significant differences between regions were seen in the rate of all-cause, AIDS and non-AIDS related mortality (global p<0.0001 for all three endpoints). Compared to South Europe, after adjusting for baseline demographics, laboratory measurements and treatment, a higher rate of AIDS related mortality was observed in East Europe (IRR 2.90, 95%CI 1.97-4.28, p<.0001), and a higher rate of non-AIDS related mortality in North Europe (IRR 1.51, 95%CI 1.24-1.82, p<.0001). The differences observed in North Europe decreased over calendar-time, in 2009-2011, the higher rate of non-AIDS related mortality was no longer significantly different to South Europe (IRR 1.07, 95%CI 0.66-1.75, pâ=â0.77). However, in 2009-2011, there remained a higher rate of AIDS-related mortality (IRR 2.41, 95%CI 1.11-5.25, pâ=â0.02) in East Europe compared to South Europe in adjusted analysis. INTERPRETATIONS: There are significant differences in the rate of all-cause mortality among HIV-positive individuals across different regions of Europe and Argentina. Individuals in Eastern Europe had an increased risk of mortality from AIDS related causes and individuals in North Europe had the highest rate of non-AIDS related mortality. These findings are important for understanding and reviewing HIV treatment strategies and policies across the European region.
Assuntos
Síndrome da Imunodeficiência Adquirida/mortalidade , Síndrome da Imunodeficiência Adquirida/virologia , Soropositividade para HIV/mortalidade , Adulto , Argentina/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Distribuição de PoissonRESUMO
BACKGROUND: A new class of antiretrovirals, AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs), has been proposed as a disease-modifying therapy to both reduce Human Immunodeficiency Virus Type 1 (HIV-1) RNA levels and the excessive immune activation now recognized as the major driver of not only the continual loss of CD4(+) T cells and progression to Acquired Immunodeficiency Syndrome (AIDS), but also of the emergence of both AIDS-defining and non-AIDS events that negatively impact upon morbidity and mortality despite successful (ie, fully suppressive) therapy. VS411, the first-in-class AV-HALT, combined low-dose, slow-release didanosine with low-dose hydroxycarbamide to accomplish both objectives with a favorable toxicity profile during short-term administration. Five dose combinations were administered as VS411 to test the AV-HALT Proof-of-Concept in HIV-1-infected subjects. METHODS: Multinational, double-blind, 28-day Phase 2a dose-ranging Proof-of-Concept study of antiviral activity, immunological parameters, safety, and genotypic resistance in 58 evaluable antiretroviral-naïve HIV-1-infected adults. Randomization and allocation to study arms were carried out by a central computer system. Results were analyzed by ANOVA, Kruskal-Wallis, ANCOVA, and two-tailed paired t tests. RESULTS: VS411 was well-tolerated, produced significant reductions of HIV-1 RNA levels, increased CD4(+) T cell counts, and led to significant, rapid, unprecedented reductions of immune activation markers after 28 days despite incomplete viral suppression and without inhibiting HIV-1-specific immune responses. The didanosine 200 mg/HC 900 mg once-daily formulation demonstrated the greatest antiviral efficacy (HIV-1 RNA: -1.47 log(10) copies/mL; CD4(+) T cell count: +135 cells/mm(3)) and fewest adverse events. CONCLUSIONS: VS411 successfully established the Proof-of-Concept that AV-HALTs can combine antiviral efficacy with rapid, potentially beneficial reductions in the excessive immune system activation associated with HIV-1 disease. Rapid reductions in markers of immune system hyperactivation and cellular proliferation were obtained despite the fact that VS411 did not attain maximal suppression of HIV RNA, suggesting this effect was due to the HALT component. TRIAL REGISTRATION: ITEudraCT 2007-002460-98.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Didanosina/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , RNA Viral/biossíntese , Ureia/análogos & derivados , Adulto , Análise de Variância , Fármacos Anti-HIV/farmacologia , Biomarcadores/metabolismo , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Preparações de Ação Retardada , Nucleotídeos de Desoxiadenina/metabolismo , Didanosina/farmacologia , Didesoxinucleotídeos/metabolismo , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/crescimento & desenvolvimento , HIV-1/imunologia , Humanos , Imunomodulação/efeitos dos fármacos , Masculino , Placebos , RNA Viral/efeitos dos fármacos , Ureia/farmacologia , Ureia/uso terapêutico , Carga ViralRESUMO
BACKGROUND: The aim of this study was to determine whether there is a protective effect of combination antiretroviral therapy (cART) on the development of clinical events in patients with ongoing severe immunosuppression. METHODS: A total of 3,780 patients from the EuroSIDA study under follow-up after 2001 with a current CD4(+) T-cell count ≤200 cells/mm(3) were stratified into five groups: group 1, viral load (VL)<50 copies/ml on cART; group 2, VL 50-99,999 copies/ml on cART; group 3, VL 50-99,999 copies/ml off cART; group 4, VL≥100,000 copies/ml on cART; and group 5, VL≥100,000 copies/ml off cART. Poisson regression was used to identify the risk of (non-fatal or fatal) AIDS- and non-AIDS-related events considered together (AIDS/non-AIDS) or separately as AIDS or non-AIDS events within each group. RESULTS: There were 428 AIDS/non-AIDS events during 3,780 person-years of follow-up. Compared with group 1, those in group 2 had a similar incidence of AIDS/non-AIDS events (incidence rate ratio [IRR] 1.04; 95% CI 0.79-1.36). Groups 3, 4 and 5 had significantly higher incidence rates of AIDS/non-AIDS events compared with group 1; incidence rates increased from group 3 (IRR 1.78; 95% CI 1.25-2.55) to group 5 (IRR 2.36; 95% CI 1.66-3.40), demonstrating the increased incidence of AIDS/non-AIDS events associated with increasing viraemia. After adjustment, the use of cART was associated with a 40% reduction in the incidence of AIDS/non-AIDS events in patients with VL 50-99,999 copies/ml (IRR 0.59; 95% CI 0.41-0.85) and in those with a VL>100,000 copies/ml (IRR 0.66; 95% CI 0.44-1.00). Similar relationships were seen for non-AIDS events and AIDS events when considered separately. CONCLUSIONS: In patients with ongoing severe immunosuppression, cART was associated with significant clinical benefits in patients with suboptimal virological control or virological failure.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Hospedeiro Imunocomprometido , Inibidores da Transcriptase Reversa/uso terapêutico , Síndrome da Imunodeficiência Adquirida/imunologia , Adulto , Contagem de Linfócito CD4 , Avaliação de Medicamentos , Quimioterapia Combinada/métodos , Feminino , Seguimentos , HIV-1/imunologia , HIV-1/patogenicidade , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Distribuição de Poisson , Estudos Prospectivos , Fatores de Risco , Carga Viral , Viremia/virologiaRESUMO
BACKGROUND: Dolutegravir (S/GSK1349572) is a new HIV-1 integrase inhibitor that has antiviral activity with once daily, unboosted dosing. SPRING-1 is an ongoing study designed to select a dose for phase 3 assessment. We present data from preplanned primary and interim analyses. METHODS: In a phase 2b, multicentre, dose-ranging study, treatment-naive adults were randomly assigned (1:1:1:1) to receive 10 mg, 25 mg, or 50 mg dolutegravir or 600 mg efavirenz. Dose but not drug allocation was masked. Randomisation was by a central integrated voice-response system according to a computer-generated code. Study drugs were given with either tenofovir plus emtricitabine or abacavir plus lamivudine. Our study was done at 34 sites in France, Germany, Italy, Russia, Spain, and the USA beginning on July 9, 2009. Eligible participants were seropositive for HIV-1, aged 18 years or older, and had plasma HIV RNA viral loads of at least 1000 copies per mL and CD4 counts of at least 200 cells per µL. Our primary endpoint was the proportion of participants with viral load of less than 50 copies per mL at week 16 and we present data to week 48. Analyses were done on the basis of allocation group and included all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00951015. FINDINGS: 205 patients were randomly allocated and received at least one dose of study drug: 53, 51, and 51 to receive 10 mg, 25 mg, and 50 mg dolutegravir, respectively, and 50 to receive efavirenz. Week 16 response rates to viral loads of at most 50 copies per mL were 93% (144 of 155 participants) for all doses of dolutegravir (with little difference between dose groups) and 60% (30 of 50) for efavirenz; week 48 response rates were 87% (139 of 155) for all doses of dolutegravir and 82% (41 of 50) for efavirenz. Response rates between nucleoside reverse transcriptase inhibitor subgroups were similar. We identified three virological failures in the dolutegravir groups and one in the efavirenz group-we did not identify any integrase inhibitor mutations. We did not identify any dose-related clinical or laboratory toxic effects, with more drug-related adverse events of moderate-or-higher intensity in the efavirenz group (20%) than the dolutegravir group (8%). We did not judge that any serious adverse events were related to dolutegravir. INTERPRETATION: Dolutegravir was effective when given once daily without a pharmacokinetic booster and was well tolerated at all assessed doses. Our findings support the assessment of once daily 50 mg dolutegravir in phase 3 trials.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/administração & dosagem , HIV-1/fisiologia , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Adulto , Idoso , Alcinos , Benzoxazinas/administração & dosagem , Ciclopropanos , Relação Dose-Resposta a Droga , Feminino , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Piridonas , RNA Viral/sangue , Inibidores da Transcriptase Reversa/administração & dosagem , Carga Viral , Replicação Viral/efeitos dos fármacos , Adulto JovemRESUMO
The HIV-1 epidemic in Russia has been insufficiently studied, with only 11 complete genome sequences from this country currently available, only three of which are of the locally predominant genetic form, the former Soviet Union (FSU) subtype A variant (A(FSU)). Here we analyze 10 newly derived A(FSU) near full-length genome sequences from Russia. Samples were selected based on phylogenetic clustering in protease-reverse transcriptase in two of the major A(FSU) clusters, V77I(PR) (n=6), widely circulating in Russia and other FSU countries, and A(SP1) (n=4), predominant in St. Petersburg. The phylogenetic analysis shows that the V77I(PR) genomes group in a monophyletic cluster together with 10 previously obtained A(FSU) genome sequences from Uzbekistan, Kazakhstan, Russia, and Cyprus, all bearing the V77I substitution in protease. Similarly, the four A(SP1) genomes group in a monophyletic cluster. These results therefore show that the monophyly of V77I(PR) and A(SP1) A(FSU) clusters is supported in near complete genomes.
Assuntos
Infecções por HIV/virologia , HIV-1/genética , Filogenia , Produtos do Gene pol do Vírus da Imunodeficiência Humana/genética , Sequência de Bases , Chipre/epidemiologia , Feminino , Variação Genética , Genoma Viral/genética , Infecções por HIV/epidemiologia , HIV-1/isolamento & purificação , Humanos , Cazaquistão/epidemiologia , Masculino , Dados de Sequência Molecular , Prevalência , Federação Russa/epidemiologia , Uzbequistão/epidemiologiaRESUMO
OBJECTIVE: To describe temporal changes in the incidence rate of tuberculosis (TB) (pulmonary or extrapulmonary) among HIV-positive patients in western Europe and risk factors of TB across Europe. METHODS: Poisson regression models were used to determine temporal changes in incidence rate of TB among 11,952 patients from western Europe (1994-2010), and to assess risk factors for TB among 12,673 patients from across Europe with follow-up after 2001. RESULTS: Two hundred and seventy-seven TB events occurred during 84,221 person-years of follow-up (PYFU) in western Europe. The incidence rate declined from 1.91 [95% confidence interval (CI) 1.51-2.37)] in 1994-1995 to 0.12 (0.07-0.21)/100 PYFU in 2002-2003, and remained stable thereafter. After January 2001, 159 TB events were diagnosed; 65 cases in western Europe and 94 cases in eastern Europe; resulting in incidence rates of 0.12 (0.09-0.14) and 0.65 (0.52-0.79)/100 PYFU, respectively. In multivariable analysis, incidence rate of TB was approximately four-fold higher in eastern Europe compared with western Europe [incidence rate ratio (IRR) 4.25 (2.78-6.49), P < 0.001]. There were no significant temporal changes after 2001 and risk factors did not differ significantly between eastern Europe and western Europe. Lower CD4 cell counts, higher HIV-RNA levels, male sex, intravenous drug usage and African origin were all associated with higher risk of TB. CONCLUSION: Incidence rates of TB in western Europe remained at a very low and stable level since 2001. After 2001, patients in eastern Europe were at substantially higher risk of TB than in western Europe. TB is of great concern in HIV-positive patients, especially in areas with high TB prevalence, high levels of immigration from TB-endemic regions, and with suboptimal access to combination antiretroviral therapy.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Infecções por HIV/mortalidade , Tuberculose/mortalidade , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Adulto , Contagem de Linfócito CD4 , Europa (Continente)/epidemiologia , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Distribuição de Poisson , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Tuberculose/tratamento farmacológico , Tuberculose/imunologiaRESUMO
BACKGROUND: This study compared the incidence of fatal and nonfatal AIDS and non-AIDS events in HIV-positive individuals with a CD4 cell count more than 350â cells/µl among viral load strata: low (<500â copies/ml), intermediate (500-9999.9â copies/ml) and high (≥ 10000â copies/ml). METHODS: Individuals contributed person-years at risk if their most recent CD4 cell count was more than 350â cells/µl. Follow-up was censored if their CD4 cell count dropped below 350â cells/µl. Poisson regression analysis investigated the relationship between viraemia and the incidence of AIDS and non-AIDS events. RESULTS: Three hundred and fifty-four AIDS events occurred during 51â732 âperson-years of follow-up (PYFU), crude incidence rate of AIDS across the three strata was 0.53, 0.90 and 2.12 per 100âPYFU, respectively. After adjustment, a higher rate of AIDS was observed in individuals with moderate [incidence rate ratio (IRR) 1.44, 1.02-2.05, Pâ=â0.03] and high viraemia had a higher rate (IRR 3.91, 2.89-5.89, Pâ<â0.0001) compared with low viraemia. Five hundred and seventy-two non-AIDS events occurred during 43â784âPYFU, the crude incidence rates were 1.28, 1.52, and 1.38 per 100âPYFU, respectively. After adjustment, particularly for age, region of Europe and starting combination antiretroviral therapy, there was a 61% (IRR 1.61, 1.21-2.14, Pâ=â0.001) and 66% (IRR 1.66, 1.17-2.32, Pâ=â0.004) higher rate of non-AIDS in individuals with intermediate and high viraemia compared with low viraemia. CONCLUSION: In individuals with a CD4 cell count more than 350â cells/µl, an increased incidence of AIDS and a slightly increased incidence of non-AIDS was found in those with uncontrolled viral replication. The association with AIDS was clear and consistent. However, the association with non-AIDS was only apparent after adjustment and no differences were observed between intermediate and high viraemia.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Síndrome da Imunodeficiência Adquirida/mortalidade , Contagem de Linfócito CD4 , HIV-1 , Carga Viral , Infecções Oportunistas Relacionadas com a AIDS/imunologia , Síndrome da Imunodeficiência Adquirida/imunologia , Adulto , Argentina/epidemiologia , Progressão da Doença , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Humanos , Incidência , Israel/epidemiologia , Masculino , Estudos Prospectivos , Fatores de Risco , ViremiaRESUMO
Subtype G has been estimated to represent the fourth most prevalent clade in the HIV-1 pandemic and subtype F is widely circulating in parts of South America (frequently within BF recombinant forms) and in Romania. However, functional envelope clones of these subtypes are lacking, which are needed for studies on antibody-mediated neutralization, coreceptor usage, and efficiency of viral entry inhibitor drugs. Here we report the construction, neutralization properties, and coreceptor usage of HIV-1 functional envelope clones of subtypes G (n = 15) and F (n = 7). These clones were obtained through RT-PCR amplification of HIV-1 gp160 from plasma RNA, and were used for pseudovirus production. All 15 subtype G-enveloped pseudoviruses were resistant to neutralization by gp120-targeted broadly neutralizing monoclonal antibodies (MAbs) b12 and 2G12, while a majority were neutralized by gp41-targeted MAbs 2F5 and 4E10. With regard to the subtype F envelopes, all seven pseudoviruses were resistant to 2F5 and b12, six were resistant to G12, and six were neutralized by 4E10. Coreceptor usage testing revealed that 21 of 22 envelopes were CCR5-tropic, including all 15 subtype G envelopes, seven of which were from patients with CD4(+) T cell counts <200/ml. These results confirm the broadly neutralizing activity of 4E10 on envelope clones across all tested group M clades, including subtypes G and F, reveal the resistance of most subtype F-enveloped pseudoviruses to broadly neutralizing MAbs b12, 2G12, and 2F5, and suggest that, similarly to subtype C, CXCR4 tropism is uncommon in subtype G, even at advanced stages of infection.