Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy.

BACKGROUND: Persons infected with human immunodeficiency virus (HIV) have an increased risk for several cancers, but the influences of behavioral risk factors, such as smoking and intravenous drug use, and highly active antiretroviral therapy (HAART) on cancer risk are not clear. METHODS: Patient records were linked between the Swiss HIV Cohort Study and Swiss cantonal cancer registries. Observed and expected numbers of incident cancers were assessed in 7304 persons infected with HIV followed for 28,836 person-years. Relative risks for cancer compared with those for the general population were determined by estimating cancer registry-, sex-, age-, and period-standardized incidence ratios (SIRs). RESULTS: Highly elevated SIRs were confirmed in persons infected with HIV for Kaposi sarcoma (KS) (SIR = 192, 95% confidence interval [CI] = 170 to 217) and non-Hodgkin lymphoma (SIR = 76.4, 95% CI = 66.5 to 87.4). Statistically significantly elevated SIRs were also observed for anal cancer (SIR = 33.4, 95% CI = 10.5 to 78.6); Hodgkin lymphoma (SIR = 17.3, 95% CI = 10.2 to 27.4); cancers of the cervix (SIR = 8.0, 95% CI = 2.9 to 17.4); liver (SIR = 7.0, 95% CI = 2.2 to 16.5); lip, mouth, and pharynx (SIR = 4.1, 95% CI = 2.1 to 7.4); trachea, lung, and bronchus (SIR = 3.2, 95% CI = 1.7 to 5.4); and skin, nonmelanomatous (SIR = 3.2, 95% CI = 2.2 to 4.5). In HAART users, SIRs for KS (SIR = 25.3, 95% CI = 10.8 to 50.1) and non-Hodgkin lymphoma (SIR = 24.2, 95% CI = 15.0 to 37.1) were lower than those for nonusers (KS SIR = 239, 95% CI = 211 to 270; non-Hodgkin lymphoma SIR = 99.3, 95% CI = 85.8 to 114). Among HAART users, however, the SIR (although not absolute numbers) for Hodgkin lymphoma (SIR = 36.2, 95% CI = 16.4 to 68.9) was comparable to that for KS and non-Hodgkin lymphoma. No clear impact of HAART on SIRs emerged for cervical cancer or non-acquired immunodeficiency syndrome-defining cancers. Cancers of the lung, lip, mouth, or pharynx were not observed among nonsmokers. CONCLUSION: In persons infected with HIV, HAART use may prevent most excess risk of KS and non-Hodgkin lymphoma, but not that of Hodgkin lymphoma and other non-acquired immunodeficiency syndrome-defining cancers. No cancers of the lip, mouth, pharynx, or lung were observed in nonsmokers.

A manipulacao de prematuros em uma Unidade de Terapia Intensiva Neonatal

Os prematuros são submetidos a diversas manipulações e procedimentos durante internação em unidades neonatais, com consequências deletérias para a saúde. O objetivo do presente estudo foi descrever a manipulação a que são submetidos os prematuros durante as 24 horas em uma unidade de terapia intensiva neonatal (UTIN). Estudo observacional, descritivo, exploratório, realizado com 20 prematuros, filmados continuamente por um período de 24 horas, de setembro de 2008 a março de 2009 numa UTIN. Os prematuros foram submetidos a uma média de 768 manipulações e 1.341 procedimentos. A manipulação durou em média 2 horas e 26 minutos em um período de 24 horas. Cada manipulação agrupou uma média de 2,2 procedimentos, a maioria no turno matutino As manipulações isoladas representaram 65,6% do total de manipulações e a maioria teve duração inferior a um minuto. Conclui-se que nas 24 horas avaliadas, os prematuros foram submetidos a um excesso de manipulações na UTIN.

Clínica do cuidado de enfermagem na terapia intensiva: aliança entre técnica, tecnologia e humanização

Pesquisa de campo, qualitativa, cujo objetivo foi caracterizar a clínica do cuidado de enfermagem específica da terapia intensiva. Para isso forma realizadas observação e entrevista com 21 enfermeiros de uma unidade de terapia intensiva. Os resultados evidenciaram oito características desta clínica, que abarcam tanto a subjetividade quanto a objetividade, traduzidas em: interação, diálogo, princípios humanísticos, vigilância, conhecimento e domínio do maquinário. Em razão dessa clínica, a subjetividade nem sempre expressa-se de modo claro e a objetividade exige capacitação dos enfermeiros para cuidar na terapia intensiva. Conclui-se que a clínica do cuidado de enfermagem na terapia intensiva alia técnica, tecnologia e humanização, que fundamentam os cuidados de enfermagem que lá se realizam.

Pharmacokinetic and pharmacogenetic factors influencing plasma and cellular antiretroviral drug disposition

Abstract: The improvement in antiretroviral drug therapy has transformed HIV infection into a chronic disease. However, treatment failure and drug toxicity are frequent. Inadequate response to treatment is clearly multifactorial and, therefore, dosage individualisation based on demographic factors, genetic markers and measurement of cellular and plasma drug level may enhance both drug efficacy and tolerability. At present, antiretroviral drugs levels are monitored in plasma, whereas only drugs penetrating into cells are able to exert an antiviral activity, suggesting that cellular drug determination may more confidently reflect drug exposure at the site of pharmacological action. The overall objective of this thesis is to provide a better understanding of the Pharmacokinetic and pharmacogenetic factors influencing the plasma and cellular disposition of antiretroviral drugs. To that endeavour, analytical methods for the measurements of plasma and cellular drug levels have been developed and validated using liquid chromatography methods coupled with ultraviolet and tandem mass spectrometry detection, respectively. Correlations between plasma and cellular exposures were assessed during observational and experimental studies. Cytochrome (CYP) 2B6, efflux transporters (ABCB1, ABCC1, ABCC2 and ABCG2) and orosomucoid (ORM) polymorphisms were determined and were related to plasma and cellular exposures, as well as toxicity of antiretroviral drugs. A Pharmacokinetic population model was developed to characterise inter- and intra-patient variability of atazanavir pharmacokinetics, and to identify covariates influencing drug disposition. In that context, a Pharmacokinetic interaction study between atazanavir and lopinavir, both boosted with ritonavir, has beén conducted to assess the safety and pharmacokinetics of this boosted double-protease inhibitors regimen. Well to moderately-correlated cellular and plasma drug levels are .observed or protease inhibitors, whereas for efavirenz and nevirapine these correlations are weak. Cellular exposure, and CYP2B6 genotype (516G>T) are predictors of efavirenz neuropsychological toxicity. Nevirapine plasma exposure is also influenced by CYPZB6 polymorphism. Nelfinavir cellular exposure appears to be significantly associated only with ABCB1 genotype (3435C>T and intron 26 + 80T>C). Indinavir and lopinavir clearance and lopinavir cellular/plasma exposure ratio are influenced by the concentration of the variant S of ORM, suggesting-a specific binding of these drugs to this variant. Nelfinavir and efavirenz are not influenced by ORM concentration and phenotype. The Pharmacokinetic parameters of atazanavir are adequately described by our population model. The atazanavir-lopinavir interaction study indicates no influence on plasma and cellular atazanavir pharmacokinetics, while limited decrease in lopinavir concentrations was observed after atazanavir addition. The residual variability unexplained by the considered variables suggests that other covariates either uncontrolled at present or remaining to be identified, such as genetic and environmental factors influence antiretroviral drug pharmacokinetics, with substantial impact on treatment efficacy and tolerability. In that context, a comprehensive approach taking into account drug pharmacokinetics and patient genetic background is expected to contribute to increase treatment success, and to reduce the occurrence of adverse drug reactions by stratifying patients in an individualised antiretroviral therapy approach. Résumé Facteurs pharmacocinétiques et pharmacogénétiques influençant l'exposition plasmatique et cellulaire des antirétroviraux Les progrès de la thérapie antirétrovirale ont transformé l'infection par le VIH d'une affection mortelle à une maladie chronique. En dépit de ce succès, l'échec thérapeutique et la toxicité médicamenteuse restent fréquents. Une réponse inadéquate au traitement est clairement multifactorielle et une individualisation de la posologie des médicaments qui se baserait sur les facteurs démographiques et génétiques des patients et sur les taux sanguins des médicaments pourrait améliorer à la fois l'efficacité et la tolérance de la thérapie. Par ailleurs, seules les concentrations plasmatiques sont actuellement considérées pour le suivi thérapeutique des médicaments, alors que les taux cellulaires pourraient mieux refléter l'activité de ses médicaments qui agissent au niveau intracellulaire. L'objectif global de cette thèse était de mieux comprendre les facteurs pharmacocinétiques et pharmacocénétiques influençant l'exposition plasmatique et cellulaire des médicaments antirétroviraux. A cet effet, des méthodes pour quantifier les concentrations plasmatiques et cellulaires des antirétroviraux ont été développées et validées en utilisant la chromatographie liquide couplée à la détection ultraviolette et la spectrométrie de masse en tandem, respectivement. La corrélation entre l'exposition cellulaire et plasmatique de ces médicaments a été étudiée lors d'études observationnelles et expérimentales. Les polymorphismes du cytochrome (CYP) 2B6, ainsi que des transporteurs d'efflux (ABCB1, ABCC1, ABCC2 et ABCG2) et de l'orosomucoïde (ORM) ont été déterminés et corrélés avec l'exposition plasmatique et cellulaire des antirétroviraux, ainsi qu'à leur toxicité. Un modèle de pharmacocinétique de population a été établi afin de caractériser la variabilité inter- et intra-individuelle de l'atazanavir, et d'identifier les covariables pouvant influencer le devenir de ce médicament. Dans ce contexte, une étude d'interaction entre l'atazanavir et le lopinavir a été effectuée afin de déterminer la sécurité et le profil pharmacocinétique de ce régime thérapeutique. Des corrélations modérées à bonnes ont été observées entre les taux cellulaires et plasmatiques des inhibiteurs de protéase, alors que pour l'efavirenz et la névirapine ces corrélations sont faibles. L'exposition cellulaire, ainsi que le génotype du CYP2B6 (516G>T) sont des indices de la toxicité neuropsychologique de l'efavirenz. L'exposition plasmatique de la névirapine est également influencée par le polymorphisme du CYPZB6. L'exposition cellulaire du nelfinavir est significativement associée au génotype du ABCB1 (3435C>T et intron 26 + 80T>C). La clairance de l'indinavir et du lopinavir, ainsi que le rapport entre exposition cellulaire et plasmatique du lopinavir sont influencés par la concentration du variant S de l'ORM, suggérant une liaison spécifique de ces médicaments à ce variant. La clairance du nelfinavir et de l'efavirenz n'est pas influencée ni par la concentration ni par le phénotype de l'ORM. Les paramètres pharmacocinétiques de l'atazanavir ont été décrits de façon adéquate par le modèle de population proposé. De plus, le lopinavir n'influence pas les concentrations plasmatiques et cellulaires de l'atazanavir; alors que celui-ci conduit à une baisse limitée des taux de lopinavir. L'importante variabilité pharmacocinétique des antirétroviraux suggère que d'autres facteurs génétiques et environnementaux -qui restent encore à découvrir- influencent également leur disponibilité. Dans un proche futur, une prise en charge qui tienne. compte de la pharmacocinétique des médicaments et des caractéristiques génétiques du patient devrait permettre d'individualiser le traitement, contribuant certainement à une amélioration de la réponse thérapeutique et à une diminution de la toxicité. Résumé grand public Facteurs pharmacocinétiques et pharmacogénétiques influençant l'exposition plasmatique et cellulaire des antirétroviraux Les progrès effectués dans le traitement de l'infection par le virus de l'immunodéficience humaine acquise (VIH), ont permis de transformer une maladie avec un pronostic sombre, en une maladie chronique traitable avec des médicaments de plus en plus efficaces. Malgré ce succès, de nombreux patients ne répondent pas de façon optimale à leur traitement et/ou souffrent d'effets indésirables médicamenteux entraînant fréquemment une modification de leur thérapie. Actuellement, le suivi de la réponse au traitement s'effectue par la mesure chez les patients de la quantité de virus et du nombre des cellules immunitaires dans le sang, ainsi que par la concentration sanguine des médicaments administrés. Cependant, comme le virus se réplique à l'intérieur de la cellule, la mesure des concentrations médicamenteuses au niveau intracellulaire pourrait mieux refléter l'activité pharmacologique au site d'action. De plus, il a été possible de mettre en évidence la grande variabilité des concentrations plasmatiques de médicaments chez des patients prenant pourtant la même dose de médicament. Comme cette variabilité est notamment due à des facteurs génétiques qui sont susceptibles d'influencer la réponse au traitement antirétroviral, des analyses génétiques ont été également effectuées chez ces patients. Cette thèse a eu pour objectif de mieux comprendre les facteurs pharmacologiques et génétiques influençant l'activité et la toxicité des médicaments antirétroviraux afin de réduire la variabilité de la réponse thérapeutique. A cet effet, une méthode de dosage permettant la quantification des médicaments anti-HIV au niveau intracellulaire a été développée. Par ailleurs, nos études ont également porté .sur les variations génétiques influençant la quantité et l'activité des protéines impliquées dans le métabolisme et dans le transport des médicaments antirétroviraux. Enfin, les conséquences de ces variations sur la réponse clinique et la toxicité du traitement ont été évaluées. Nos études ont mis en évidence des associations significatives entre les variations génétiques considérées et la concentration sanguine, cellulaire et la toxicité de quelques médicaments antirétroviraux. La complémentarité des connaissances pharmacologiques, génétiques et virales pourrait aboutir à une stratégie globale permettant d'individualiser le traitement et la dose administrée, en fonction des caractéristiques propres de chaque patient. Cette approche pourrait contribuer à une optimisation du traitement antirétroviral dans la perspective d'une meilleure- efficacité thérapeutique à long terme et d'une diminution des effets indésirables rencontrés.

HIV-1 Subtype Is an Independent Predictor of Reverse Transcriptase Mutation K65R in HIV-1 Patients Treated with Combination Antiretroviral Therapy Including Tenofovir.

Subtype-dependent selection of HIV-1 reverse transcriptase resistance mutation K65R was previously observed in cell culture and small clinical investigations. We compared K65R prevalence across subtypes A, B, C, F, G, and CRF02_AG separately in a cohort of 3,076 patients on combination therapy including tenofovir. K65R selection was significantly higher in HIV-1 subtype C. This could not be explained by clinical and demographic factors in multivariate analysis, suggesting subtype sequence-specific K65R pathways.

Incidência de úlceras por pressão em pacientes de Unidade de Terapia Intensiva Cardiopneumológica

RESUMO Objetivo Identificar e analisar os coeficientes de incidência de úlceras por pressão (UP) e os fatores de risco para o seu desenvolvimento em pacientes críticos com doenças cardiopneumológicas. Método Estudo de coorte, prospectivo realizado na Unidade de Terapia Intensiva (UTI) Cardiopneumológica de um hospital de grande porte na cidade de São Paulo, durante os meses de novembro de 2013 a fevereiro de 2014. Participaram do estudo 370 pacientes maiores de 18 anos, que não apresentavam UP na admissão e que estavam na UTI há menos de 24 horas. Os dados foram analisados por meio de análises univariadas e multivariada (Classification And Regression Tree - CART). Resultados Os coeficientes de incidência de UP foram: 11,0% para o total, distribuindo-se em 8,0% entre os homens e 3,0% para as mulheres (p=0,018); 10,0% na raça branca e 6,5% em pessoas com idade igual e superior a 60 anos. Os principais fatores de risco encontrados foram tempo de permanência na UTI igual ou superior a 9,5 dias, idade igual ou superior a 42,5 anos e raça branca. Conclusão O estudo contribui para os conhecimentos relacionados à epidemiologia das UP em pacientes críticos com doenças cardiopneumológicas, favorecendo o planejamento de cuidados preventivos específicos para essa clientela.

Carga de trabalho de enfermagem: preditor de infecção relacionada à assistência à saúde na terapia intensiva?

RESUMO Objetivo Analisar a influência da carga de trabalho de enfermagem na ocorrência de infecção relacionada à assistência à saúde (IRAS) em pacientes na Unidade de Terapia Intensiva (UTI), segundo o tipo de tratamento. Método Estudo de coorte retrospectivo desenvolvido em nove UTI em São Paulo, Brasil, de setembro a dezembro de 2012. A carga de trabalho de enfermagem foi mensurada pelo Nursing Activities Score (NAS). Os testes T-Student, Exato de Fisher e regressões logísticas foram utilizados nas análises. Resultados A casuística foi composta por 835 pacientes (54,3±17,3 anos; 57,5% do sexo masculino), dentre os quais 12,5% adquiriram IRAS na UTI. O NAS dos pacientes admitidos para tratamento clínico foi de 71,3±10,9 e para cirúrgico, 71,6±9,2. O tempo de permanência na unidade e a gravidade foram fatores preditivos para ocorrência de IRAS em pacientes admitidos nas UTI para tratamento clínico ou cirúrgico e o sexo masculino apenas para pacientes cirúrgicos. Ao considerar as admissões independentes do tipo de tratamento, além das variáveis citadas, o índice de comorbidades também permaneceu no modelo de regressão. O NAS não foi fator preditivo de IRAS. Conclusão A carga de trabalho de enfermagem não exerceu influência na ocorrência de IRAS nos pacientes deste estudo.

Estresse, coping e burnout da Equipe de Enfermagem de Unidades de Terapia Intensiva: fatores associados

RESUMO Objetivo Investigar o estresse emocional, o coping e burnout da equipe de enfermagem e a associação com fatores biossociais e do trabalho em Unidade de Terapia Intensiva (UTI). Método Estudo transversal, realizado em oito UTI de hospital-escola, do município de São Paulo, em 2012. Coletaram-se dados biossociais e de trabalho dos profissionais, juntamente com Escalas de Estresse no Trabalho, Coping Ocupacional, Lista de Sinais e Sintomas e Inventário Maslach de Burnout. Resultados Participaram da pesquisa 287 sujeitos, predominantemente mulheres, com companheiro e filhos. O nível médio de estresse e coping controle foram prevalentes (74,47% e 79,93%, respectivamente) e a presença de burnout em 12,54%. Fatores associados ao estresse referiram-se às condições de trabalho. Ter companheiro, atuar em UTI Clínica e gostar do trabalho foram fatores de proteção para coping prevalente, enquanto que horas de sono adequadas foi fator de proteção para burnout. Conclusão O controle do ambiente de trabalho e o sono adequado são fatores decisivos e protetores para enfrentamento das situações de estresse ocupacional.

Cultura e clima organizacional para segurança do paciente em Unidades de Terapia Intensiva

RESUMO Objetivo Avaliar a percepção dos profissionais de saúde sobre o clima e a cultura de segurança do paciente em Unidades de Terapia Intensiva (UTI) e a relação entre os instrumentos Hospital Survey on Patient Safety Culture (HSOPSC) e o Safety Attitudes Questionnaire (SAQ). Método Estudo transversal realizado em hospital de ensino no interior do estado de São Paulo, Brasil, em março/abril de 2014. Aplicaram-se o HSOPSC, o SAQ e um instrumento para levantamento das informações sociodemográficas e profissionais aos funcionários das UTI adulto, pediátrica e neonatal. A análise utilizou a estatística descritiva. Resultados As escalas apresentaram boa confiabilidade. Maiores fragilidades para a segurança do paciente foram observadas nos domínios “condições de trabalho” e “percepções da gerência” do SAQ e “resposta não punitiva aos erros” do HSOPSC. As fortalezas no SAQ foram o “clima de trabalho em equipe” e a “satisfação no trabalho” e para o HSOPSC “expectativas e ações de promoção de segurança supervisores/gerentes” e “aprendizado organizacional e melhoria mútua”. Na UTI Neonatal houve maior satisfação no trabalho do que nas demais UTI. A UTI Adulto apresentou menores pontuações para a maioria dos domínios do SAQ e HSOPSC. A correlação entre as escalas foi de força moderada (r=0,66). Conclusão Há diferenças de percepções quanto à segurança do paciente entre as UTI, o que corrobora com a existência de microculturas locais. O estudo não demonstra que o SAQ e o HSOPSC sejam equivalentes.

Segurança do paciente em Unidades de Terapia Intensiva: desenvolvimento de um projeto de pesquisa

RESUMO Objetivo Relatar a experiência sobre os diferentes processos envolvidos no desenvolvimento de um Projeto de Pesquisa em Segurança do Paciente em Unidades de Terapia Intensiva. Método Estudo com delineamento misto: coorte histórica para a coleta dos dados dos pacientes e eventos adversos/incidentes e transversal para a coleta dos dados da equipe de enfermagem. A coleta de dados ocorreu durante 90 dias, em 2012, no Instituto Central do Hospital das Clínicas da Universidade de São Paulo e o Hospital Universitário da Universidade de São Paulo. Processos desenvolvidos A pesquisa envolveu diversas etapas para sua efetivação: implantação doNursing Activities Score (NAS) no Instituto Central do Hospital das Clínicas da Universidade de São Paulo, desenvolvimento de sistema de banco de dados, digitalização de prontuários, treinamento de monitores, extração e carga de dados dos pacientes e coleta de dados durante a passagem de plantão, prontuários. Considerações finais Treinamentos, comprometimento dos pesquisadores e parceria com profissionais da tecnologia da informação foram fundamentais para a qualidade dos resultados obtidos e da produção científica alcançada. Espera-se que esse relato de experiência possa orientar e encorajar os pesquisadores a realizar pesquisas complexas que contribuam para a construção do conhecimento na enfermagem e saúde.

Limited clinical benefit of minority K103N and Y181C-variant detection in addition to routine genotypic resistance testing in antiretroviral therapy-naive patients.

OBJECTIVE: The presence of minority nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 variants prior to antiretroviral therapy (ART) has been linked to virologic failure in treatment-naive patients. DESIGN: We performed a large retrospective study to determine the number of treatment failures that could have been prevented by implementing minority drug-resistant HIV-1 variant analyses in ART-naïve patients in whom no NNRTI resistance mutations were detected by routine resistance testing. METHODS: Of 1608 patients in the Swiss HIV Cohort Study, who have initiated first-line ART with two nucleoside reverse transcriptase inhibitors (NRTIs) and one NNRTI before July 2008, 519 patients were eligible by means of HIV-1 subtype, viral load and sample availability. Key NNRTI drug resistance mutations K103N and Y181C were measured by allele-specific PCR in 208 of 519 randomly chosen patients. RESULTS: Minority K103N and Y181C drug resistance mutations were detected in five out of 190 (2.6%) and 10 out of 201 (5%) patients, respectively. Focusing on 183 patients for whom virologic success or failure could be examined, virologic failure occurred in seven out of 183 (3.8%) patients; minority K103N and/or Y181C variants were present prior to ART initiation in only two of those patients. The NNRTI-containing, first-line ART was effective in 10 patients with preexisting minority NNRTI-resistant HIV-1 variant. CONCLUSION: As revealed in settings of case-control studies, minority NNRTI-resistant HIV-1 variants can have an impact on ART. However, the implementation of minority NNRTI-resistant HIV-1 variant analysis in addition to genotypic resistance testing (GRT) cannot be recommended in routine clinical settings. Additional associated risk factors need to be discovered.

Development and Validation of Decision Rules to Guide Frequency of Monitoring CD4 Cell Count in HIV-1 Infection before Starting Antiretroviral Therapy.

Background: Although CD4 cell count monitoring is used to decide when to start antiretroviral therapy in patients with HIV-1 infection, there are no evidence-based recommendations regarding its optimal frequency. It is common practice to monitor every 3 to 6 months, often coupled with viral load monitoring. We developed rules to guide frequency of CD4 cell count monitoring in HIV infection before starting antiretroviral therapy, which we validated retrospectively in patients from the Swiss HIV Cohort Study.Methodology/Principal Findings: We built up two prediction rules ("Snap-shot rule" for a single sample and "Track-shot rule" for multiple determinations) based on a systematic review of published longitudinal analyses of CD4 cell count trajectories. We applied the rules in 2608 untreated patients to classify their 18 061 CD4 counts as either justifiable or superfluous, according to their prior >= 5% or < 5% chance of meeting predetermined thresholds for starting treatment. The percentage of measurements that both rules falsely deemed superfluous never exceeded 5%. Superfluous CD4 determinations represented 4%, 11%, and 39% of all actual determinations for treatment thresholds of 500, 350, and 200x10(6)/L, respectively. The Track-shot rule was only marginally superior to the Snap-shot rule. Both rules lose usefulness for CD4 counts coming near to treatment threshold.Conclusions/Significance: Frequent CD4 count monitoring of patients with CD4 counts well above the threshold for initiating therapy is unlikely to identify patients who require therapy. It appears sufficient to measure CD4 cell count 1 year after a count > 650 for a threshold of 200, > 900 for 350, or > 1150 for 500x10(6)/L, respectively. When CD4 counts fall below these limits, increased monitoring frequency becomes advisable. These rules offer guidance for efficient CD4 monitoring, particularly in resource-limited settings.

Impact of antiretroviral therapy (ART), immunosuppression and viraemia on lipid levels: the D:A:D study

Purpose of the study: To investigate the impact of ART, HIV viremia and immunosuppression on triglyceride (TG), total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) levels. Methods: We considered the cross-sectional associations between TG, TC and HDL-C (mmol/l; first available measurement on/after enrolment in the D:A:D study) and use of ART, HIV viral load (VL; copies/ml), and CD4 count (cells/mm3) measured at the same time. TG was log10 transformed to ensure normality. Analyses were performed using linear regression and adjusted for other factors known to impact lipid levels (table footnote). ART and VL status were combined (off ART&VL _100,000, off ART&VL B100,000, on ART&VL B500, on ART&VL _500), current and nadir CD4 count were categorised as B200, 200_349, 350_499 and _500. Summary of results: 44,322/49,734 participants in the D:A:D Study (89.1%) contributed a TG measurement (median; IQR 1.52; 1.00_ 2.45), 45,169 (90.8%) a TC measurement (4.80; 4.00_5.70) and 38,604 (77.6%) a HDL-C measurement (1.12; 0.90_1.40). Most participants were male (74%), of white ethnicity (51%), without AIDS (78%), were not receiving lipid-lowering drugs (4%) and were ART experienced (61%) with 47% previously exposed to PIs, 61% previously exposed to NRTIs and 29% previously exposed to NNRTIs. The median (IQR) age, current CD4 count and CD4 nadir were 38 (36_45) years, 400 (242_590) cells/ml and 240 (100_410) cells/ml respectively. Compared to those on ART with a suppressed VL, all lipids were lower for those off ART (Table); non-suppressive ART was also associated with lower TC and HDL-C levels (no impact on TG). A low current CD4 count was associated with lower lipid levels, whereas a low nadir CD4 count was associated with higher TC and TG levels. Prior AIDS diagnosis was associated with higher TG and TC, but lower HDL-C levels. Conclusion: Although specific drug classes were not considered, lipid levels are considerably higher in those on a suppressive ART regimen. The higher TC/TG and lower HDL-C levels seen among those with low nadir CD4 count and with a prior AIDS diagnosis suggests severe immunosuppression may be associated with dyslipidaemia over the long-term.

Influence of noninjecting and injecting drug use on mortality, retention in the cohort, and antiretroviral therapy, in participants in the Swiss HIV Cohort Study.

OBJECTIVES: We studied the influence of noninjecting and injecting drug use on mortality, dropout rate, and the course of antiretroviral therapy (ART), in the Swiss HIV Cohort Study (SHCS). METHODS: Cohort participants, registered prior to April 2007 and with at least one drug use questionnaire completed until May 2013, were categorized according to their self-reported drug use behaviour. The probabilities of death and dropout were separately analysed using multivariable competing risks proportional hazards regression models with mutual correction for the other endpoint. Furthermore, we describe the influence of drug use on the course of ART. RESULTS: A total of 6529 participants (including 31% women) were followed during 31 215 person-years; 5.1% participants died; 10.5% were lost to follow-up. Among persons with homosexual or heterosexual HIV transmission, noninjecting drug use was associated with higher all-cause mortality [subhazard rate (SHR) 1.73; 95% confidence interval (CI) 1.07-2.83], compared with no drug use. Also, mortality was increased among former injecting drug users (IDUs) who reported noninjecting drug use (SHR 2.34; 95% CI 1.49-3.69). Noninjecting drug use was associated with higher dropout rates. The mean proportion of time with suppressed viral replication was 82.2% in all participants, irrespective of ART status, and 91.2% in those on ART. Drug use lowered adherence, and increased rates of ART change and ART interruptions. Virological failure on ART was more frequent in participants who reported concomitant drug injections while on opiate substitution, and in current IDUs, but not among noninjecting drug users. CONCLUSIONS: Noninjecting drug use and injecting drug use are modifiable risks for death, and they lower retention in a cohort and complicate ART.

Association of different lipid measures for atherogenic lipid fractions and risk of coronary events in patients receiving combination antiretroviral therapy: the Swiss HIV Cohort Study

Background: Evidence for a better performance of different highly atherogenic versus traditional lipid parameters for coronary heart disease (CHD) risk prediction is conflicting. We investigated the association of the ratios of sma11 dense low density lipoprotein(LDL)/apoplipoprotein A, aolipoprotein B/apolipoprotein A-I and total cholesterol! HDL-cholesterol and CHD events in patients on combination antiretroviral therapy (cART).Methods: Case control study nested into the Swiss HIV Cohort Study: for each cART-treated patient with a first coronary event between April 1, 2000 and July 31, 2008 (case) we selected four control patients (1) that were without coronary events until the date of the event of the index case, (2) had a plasma sample within ±30 days of the sample date of the respective case, (3) received cART and (4) were then matched for age, gender and smoking status. Lipoproteins were measured by ultracentrifugation. Conditional logistic regression models were used to estimate the independent effects of different lipid ratios and the occurrence of coronary events.Results: In total, 98 cases (19 fatal myocardial infarctions [MI] and 79 non-fatal coronary events [53 definite MIs, 15 possible MIs and 11 coronary angioplasties or bypassesJ) were matched with 392 controls. Cases were more often injecting drug users, less likely to be virologically suppressed and more often on abacavir-containing regimens. In separa te multivariable models of total cholesterol, triglycerides, HDL-cholesterol, systolic blood pressure, abdominal obesity, diabetes and family history of CHD, small dense-LDL and apolipoprotein B were each statistically significantly associated with CHD events (for 1 mg/dl increase: odds ratio [OR] 1.05, 95% CI 1.00-1.11 and 1.15, 95% CI 1.01-1.31, respectively), but the ratiosof small dense-LDLlapolipoprotein A-I (OR 1.26, 95% CI 0.95-1.67), apolipoprotein B/apolipoprotein A-I (OR 1.02, 95% CI 0.97-1.07) and HDL-cholesterol! total cholesterol (OR 0.99 95% CI 0.98-1.00) were not. Following adjustment for HIV related and cART variables these associations were weakened in each model: apolipoprotein B (OR 1.27, 95% CI 1.00-1.30), sd-LDL (OR 1.04, 95% CI 0.99-1.20), small dense-LDLlapolipoprotein A-I (OR 1.17, 95% CI 0.87-1.58), apolipoprotein B/apolipoprotein A-I (OR 1.02, 95% CI 0.97-1.07) and total cholesterolJHDL- cholesterol (OR 0.99, 95% CI 0.99-1.00).Conclusions: In patients receiving cART, small dense-LDL and apolipoprotein B showed the strongest associations with CHD events in models controlling for traditional CHD risk factors including total cholesterol and triglycerides. Adding small dense LDLlapoplipoprotein A-l, apolipoprotein B/apolipoprotein A-I and total cholesterol! HDL-cholesterol ratios did not further improve models of lipid parameters and associations of increased risk for CHD events.