Prevalencia de interacciones medicamentosas con fármacos anti-retrovirales en Buenos Aires, Argentina / Prevalence of potential drug-drug interactions involving antiretroviral drugs in Buenos Aires, Argentina

Introduction: Antiretroviral agents (ARVs) have a high potential for drug interactions. However, the prevalence and risk factors for clinically significant drug-drug interactions (CSDDIs) with ARVs from Latin American countries is unknown. Aim: To evaluate the prevalence and risk factors for CSDDIs in HIV outpatients attending at two centers in Buenos Aires, Argentina. Methods: Descriptive cross-sectional study (september to november 2012). HIV-1 infected patients under ARV treatment at the time of the study were randomly assessed for concomitant medication. CSDDIs were screened using the University of Liverpool Drug Interactions Program (www.hiv-druginteractions.org). Results: A total of 217 patients were included. Male sex: 64% (CI 95: 57-70). Median age (IQR): 41 (36-48). Presence of comorbidities: 19%. ARV regimen: NNRTI-based: 48%, PI-based: 50% and NNRTI plus PI: 2%. Median of CD4 T-cell count (IQR): 402 cells/mL (235-588). Viral load < 50 copies/mL: 78%. Overall, 64% (CI 95: 57-70) of patients had > 1 co-medication of whom a 49% had at least one CSDDI. Two patients had a CSDDI between ARVs. The most frequent co-medications observed were antimicrobial (40%), cardiovascular (25%) and gastrointestinal agents (22%). In the multivariate analysis the number of co-medications and use of CNS agents were associated with the presence of CSDDIs. Conclusions: Co-medications and CSDDIs were common in our setting. In this context, training of HIV physicians in drug interactions is of major importance for adequate management of these patients.

Introducción: Los fármacos anti-retrovirales (ARVs) tienen un alto potencial de interaccionar farmacológicamente con otros medicamentos. Sin embargo, los datos sobre la prevalencia y los factores de riesgo para la presencia de interacciones medicamentosas clínicamente significativas (IMCS) con ARVs en países latinoamericanos son limitados. Objetivo: Evaluar la prevalencia y los factores de riesgo para estas IMCS en dos centros de atención ambulatoria en Buenos Aires, Argentina. Métodos: Estudio transversal y descriptivo (septiembre-noviembre de 2012). Se evaluó la presencia de medicación concomitante en pacientes infectados por VIH bajo tratamiento ARV. Para evaluar la presencia de IMCS se utilizó la base de datos de interacciones de la Universidad de Liverpool (www.hiv-druginteractions.org). Resultados: Se incluyeron 217 pacientes. Sexo masculino: 64% (IC 95: 57-70). Mediana de edad (IQR): 41 (36-48). Presencia de co-morbilidades: 19%. Tratamiento ARV basado en INNTI: 48%, basado en IP: 50% y basado en INNTI más IP: 2%. Mediana de linfocitos T-CD4 (IQR): 402 céls/ml (235-588). Carga viral < 50 copias/ml: 78%. El 64% (IC 95: 57-70) de los pacientes tenían > 1 medicación concomitante: antimicrobianos (40%), fármacos cardiovasculares (25%) y gastrointestinales (22%). De los pacientes que presentaban medicación concomitante 68 (49%) tenían > 1 IMCS y sólo tres (2%) presentaban una asociación contraindicada. Además, dos pacientes tenían una IMCS entre ARVs. En el análisis multivariado, el número de medicamentos concomitantes y el uso psicofármacos se asociaron con una mayor chance de presentar IMCS. Conclusiones: La presencia de medicación concomitante e IMCS fue común en nuestra población. En este contexto, la formación de profesionales de la salud en la detección de interacciones medicamentosas es de suma importancia para un manejo adecuado de pacientes con infección por VIH que reciban tratamiento ARV.

[Prevalence of potential drug-drug interactions involving antiretroviral drugs in Buenos Aires, Argentina]. / Prevalencia de interacciones medicamentosas con fármacos anti-retrovirales en Buenos Aires, Argentina.

INTRODUCTION: Antiretroviral agents (ARVs) have a high potential for drug interactions. However, the prevalence and risk factors for clinically significant drug-drug interactions (CSDDIs) with ARVs from Latin American countries is unknown. AIM: To evaluate the prevalence and risk factors for CSDDIs in HIV outpatients attending at two centers in Buenos Aires, Argentina. METHODS: Descriptive cross-sectional study (september to november 2012). HIV-1 infected patients under ARV treatment at the time of the study were randomly assessed for concomitant medication. CSDDIs were screened using the University of Liverpool Drug Interactions Program (www.hiv-druginteractions.org). RESULTS: A total of 217 patients were included. Male sex: 64% (CI 95: 57-70). Median age (IQR): 41 (36-48). Presence of comorbidities: 19%. ARV regimen: NNRTI-based: 48%, PI-based: 50% and NNRTI plus PI: 2%. Median of CD4 T-cell count (IQR): 402 cells/mL (235-588). Viral load < 50 copies/mL: 78%. Overall, 64% (CI 95: 57-70) of patients had > 1 co-medication of whom a 49% had at least one CSDDI. Two patients had a CSDDI between ARVs. The most frequent co-medications observed were antimicrobial (40%), cardiovascular (25%) and gastrointestinal agents (22%). In the multivariate analysis the number of co-medications and use of CNS agents were associated with the presence of CSDDIs. CONCLUSIONS: Co-medications and CSDDIs were common in our setting. In this context, training of HIV physicians in drug interactions is of major importance for adequate management of these patients.

Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study.

BACKGROUND: Dolutegravir (GSK1349572), a once-daily HIV integrase inhibitor, has shown potent antiviral response and a favourable safety profile. We evaluated safety, efficacy, and emergent resistance in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV-1 with at least two-class drug resistance. METHODS: ING111762 (SAILING) is a 48 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began in October, 2010. Eligible patients had two consecutive plasma HIV-1 RNA assessments of 400 copies per mL or higher (unless >1000 copies per mL at screening), resistance to two or more classes of antiretroviral drugs, and had one to two fully active drugs for background therapy. Participants were randomly assigned (1:1) to once-daily dolutegravir 50 mg or twice-daily raltegravir 400 mg, with investigator-selected background therapy. Matching placebo was given, and study sites were masked to treatment assignment. The primary endpoint was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48, evaluated in all participants randomly assigned to treatment groups who received at least one dose of study drug, excluding participants at one site with violations of good clinical practice. Non-inferiority was prespecified with a 12% margin; if non-inferiority was established, then superiority would be tested per a prespecified sequential testing procedure. A key prespecified secondary endpoint was the proportion of patients with treatment-emergent integrase-inhibitor resistance. The trial is registered at ClinicalTrials.gov, NCT01231516. FINDINGS: Analysis included 715 patients (354 dolutegravir; 361 raltegravir). At week 48, 251 (71%) patients on dolutegravir had HIV-1 RNA less than 50 copies per mL versus 230 (64%) patients on raltegravir (adjusted difference 7·4%, 95% CI 0·7 to 14·2); superiority of dolutegravir versus raltegravir was then concluded (p=0·03). Significantly fewer patients had virological failure with treatment-emergent integrase-inhibitor resistance on dolutegravir (four vs 17 patients; adjusted difference -3·7%, 95% CI -6·1 to -1·2; p=0·003). Adverse event frequencies were similar across groups; the most commonly reported events for dolutegravir versus raltegravir were diarrhoea (71 [20%] vs 64 [18%] patients), upper respiratory tract infection (38 [11%] vs 29 [8%]), and headache (33 [9%] vs 31 [9%]). Safety events leading to discontinuation were infrequent in both groups (nine [3%] dolutegravir, 14 [4%] raltegravir). INTERPRETATION: Once-daily dolutegravir, in combination with up to two other antiretroviral drugs, is well tolerated with greater virological effect compared with twice-daily raltegravir in this treatment-experienced patient group. FUNDING: ViiV Healthcare.

Acute retroviral syndrome and high baseline viral load are predictors of rapid HIV progression among untreated Argentinean seroconverters.

BACKGROUND: Diagnosis of primary HIV infection (PHI) has important clinical and public health implications. HAART initiation at this stage remains controversial. METHODS: Our objective was to identify predictors of disease progression among Argentinean seroconverters during the first year of infection, within a multicentre registry of PHI-patients diagnosed between 1997 and 2008. Cox regression was used to analyze predictors of progression (LT-CD4 < 350 cells/mm3, B, C events or death) at 12 months among untreated patients. RESULTS: Among 134 subjects, 74% presented with acute retroviral syndrome (ARS). Seven opportunistic infections (one death), nine B events, and 10 non-AIDS defining serious events were observed. Among the 92 untreated patients, 24 (26%) progressed at 12 months versus three (7%) in the treated group (p = 0.01). The 12-month progression rate among untreated patients with ARS was 34% (95% CI 22.5-46.3) versus 13% (95% CI 1.1-24.7) in asymptomatic patients (p = 0.04). In univariate analysis, ARS, baseline LT-CD4 < 350 cells/mm3, and baseline and six-month viral load (VL) > 100,000 copies/mL were associated with progression. In multivariate analysis, only ARS and baseline VL > 100,000 copies/mL remained independently associated; HR: 8.44 (95% CI 0.97-73.42) and 9.44 (95% CI 1.38-64.68), respectively. CONCLUSIONS: In Argentina, PHI is associated with significant morbidity. HAART should be considered in PHI patients with ARS and high baseline VL to prevent disease progression.

Predicted susceptibility of etravirine in HIV patients experiencing virological failure secondary to non-nucleoside reverse transcriptase inhibitor resistance in Argentina

Introducción La respuesta virológica a etravirina (ETR) depende del tipo y número de mutaciones asociadas a resistencia (RAM) a los inhibidores no nucleósidos de la transcriptasa inversa (NNRTI). Métodos Los NNRTI utilizados en el TARGA al momento del fallo virológico y el número y tipo de mutaciones a NNRTI se recogieron y analizaron retrospectivamente. Se incluyó como ETR-RAM las siguientes mutaciones: V90I, A98G, L100I, K101E/H/P, V106I, E138A, V179D/F/T, Y181C/I/V, G190A / S, y M230L, las cuales fueron analizadas de acuerdo con la puntuación ponderada de mutación para predecir la susceptibilidad a etravirina (Vingerhoets 2008). Resultados N = 150. El TARGA incluía: efavirenz (EFV) 76,7%, nevirapina (NVP): 23,3%. Frecuencia ETR-RAMs: cero = 38,7%, uno = 39,3%, dos = 17,3%, tres = 3,3%, cuatro = 1,3%. ETR-RAMs más frecuentes después de fallo virológico con EFV: G190A (28,1%), K101E (14,9%), L100I (10,5%), y con NVP: Y181C (41,7%), G190A (30,6%) y A98G (13,9%). Susceptibilidad a ETR: máxima respuesta: 69,3%, respuesta intermedia: 24,7%, respuesta disminuida: 6%. Comparando máxima respuesta con duración del fallo virológico: EFV: 94,4% (<24 semanas) vs. 69,8% (> 24 semanas) (p = 0,02), y NVP: 42,9% (<24 semanas) vs. 56,5% (> 24 semanas) (p = 0,41). El uso de lamivudina fue asociado a una mayor susceptibilidad a ETR (máxima respuesta) (79% vs. 25%; p=0,001)Discusión La mayoría de los pacientes mantienen susceptibilidad a ETR tras la adquisición de resistencia a un NNRTI. El fallo virológico con EFV con lleva una mayor susceptibilidad a ETR que con NVP, especialmente cuando el fracaso virológico es de corto plazo (AU)

Introduction: Virological response to etravirine (ETR) is dependent on the type and number of non nucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs). Methods: Data on NNRTI used in HAART at the time of failure and the number of NNRTI-RAMs were collected and retrospectively analyzed. ETR-RAMs were defined as V90I, A98G, L100I, K101E/H/P, V106I,E138A, V179D/F/T, Y181C/I/V, G190A/S, and M230L, and were analyzed according to the weighted mutation score to predict susceptibility (Vingerhoets 2008). Results: N=150. Efavirenz (EFV) containing regimen: 76.7%; nevirapine (NVP): 23.3%. Frequency of ETRRAMs acquired after NNRTI failure: zero=38.7%, one=39.3%, two=17.3%, three=3.3%, four=1.3%. Most frequent ETR-RAMs after failure with EFV: G190A (28.1%), K101E (14.9%), L100I (10.5%); and with NVP:Y181C (41.7%), G190A (30.6%) and A98G (13.9%). Global predicted susceptibility of ETR: highest response:69.3%, intermediate response: 24.7%, reduced response: 6%. Comparing maximal response with duration of virological failure: EFV-containing regimen: 94.4% (< 24-weeks) vs. 69.8% (>24-weeks) (p=0.02); NVP containing regimen: 42.9% (< 24-weeks) vs. 56.5% (>24-weeks) (p=0.41). The presence of lamivudine regimen was associated with a better predicted susceptibility (highest response) to ETR (79% vs. 25%;P=.001). Discussion: The majority of patients maintained susceptibility to ETR after the acquisition of NNRTI resistance. Failing with an EFV-containing regimen had a better predicted susceptibility to ETR than with NVP, especially after short-term virological failure (AU)

Experiencia en el abordaje de pacientes con profilaxis posexposición no ocupacional al VIH / Experience with patients seeking post-exposure prophylaxis against HIV after non-occupational accidents

Introducción: El objetivo es analizar los datos epidemiológicos y las conductas sexuales de una cohorte de adultos sanos que recibieron profilaxis posexposición no ocupacional (PPENO) al VIH. Métodos: Se analizaron todos los individuos que concurrieron a la Unidad de Consultorios Externos del Hospital de Enfermedades Infecciosas F. J. Muñiz y que requirieron PPENO desde diciembre de 2004 a diciembre de 2008. Se evaluaron los datos demográficos, el tipo de exposición, el conocimiento de la fuente y el uso de preservativo. Se realizaron pruebas no paramétricas; se definió el nivel de significación como p = 0.05. Cuando fue posible, se analizó el riesgo relativo y los odds ratios. Resultados: Se asistieron 1318 personas, 499 mujeres, con un promedio de edad de 30.4 años mediana: 28.0. Tipo de exposición: sexual: 1054 (80.0%), sangre: 247 (18.7%), sexual y sanguínea: 14 (1.1%), sin datos: 3 (0.2%). No se encontraron diferencias estadísticamente significativas entre el sexo y el tipo de exposición, ni entre la edad y el tipo de exposición. Se conocía al individuo fuente en 413 casos (31.3%); no lo conocían 897 (68.1%); sin datos: 8 (0.6%). El conocimiento de la fuente fue mayor en las mujeres (35.6%). El promedio de edad fue mayor entre aquellos que conocían la fuente (31.3 años) en comparación con los que no la conocían (28.8). Usaron preservativos 859 casos (65.2%). Su empleo fue mayor entre hombres que no conocían la fuente y entre aquellos de mayor edad; sin embargo, la mayor edad no estuvo necesariamente asociada con el uso de preservativo. El tiempo medio desde la exposición hasta la consulta fue de 1.9 día, sin cambios durante el período estudiado. No se encontraron diferencias estadísticamente significativas en el tiempo entre la exposición accidental y la consulta en relación con el sexo o con la edad.

Predicted susceptibility of etravirine in HIV patients experiencing virological failure secondary to non-nucleoside reverse transcriptase inhibitor resistance in Argentina.

INTRODUCTION: Virological response to etravirine (ETR) is dependent on the type and number of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs). METHODS: Data on NNRTI used in HAART at the time of failure and the number of NNRTI-RAMs were collected and retrospectively analyzed. ETR-RAMs were defined as V90I, A98G, L100I, K101E/H/P, V106I, E138A, V179D/F/T, Y181C/I/V, G190A/S, and M230L, and were analyzed according to the weighted mutation score to predict susceptibility (Vingerhoets 2008). RESULTS: N=150. Efavirenz (EFV) containing regimen: 76.7%; nevirapine (NVP): 23.3%. Frequency of ETR-RAMs acquired after NNRTI failure: zero=38.7%, one=39.3%, two=17.3%, three=3.3%, four=1.3%. Most frequent ETR-RAMs after failure with EFV: G190A (28.1%), K101E (14.9%), L100I (10.5%); and with NVP: Y181C (41.7%), G190A (30.6%) and A98G (13.9%). Global predicted susceptibility of ETR: highest response: 69.3%, intermediate response: 24.7%, reduced response: 6%. Comparing maximal response with duration of virological failure: EFV-containing regimen: 94.4% (< 24-weeks) vs. 69.8% (>24-weeks) (p=0.02); NVP-containing regimen: 42.9% (< 24-weeks) vs. 56.5% (>24-weeks) (p=0.41). The presence of lamivudine regimen was associated with a better predicted susceptibility (highest response) to ETR (79% vs. 25%; P=.001). DISCUSSION: The majority of patients maintained susceptibility to ETR after the acquisition of NNRTI resistance. Failing with an EFV-containing regimen had a better predicted susceptibility to ETR than with NVP, especially after short-term virological failure.

Similar safety and efficacy of once- and twice-daily lopinavir/ritonavir tablets in treatment-experienced HIV-1-infected subjects at 48 weeks.

OBJECTIVES: To compare the safety and antiviral activity of once (QD) or twice (BID) daily lopinavir/ritonavir (LPV/r) in combination with investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in treatment-experienced subjects. METHODS: Subjects failing treatment with HIV-1 RNA > 1000 copies per milliliter received LPV/r tablets 800/200 mg QD (n = 300) or 400/100 mg BID (n = 299) with investigator-chosen nucleoside/nucleotide reverse transcriptase inhibitors. Efficacy was determined by the intent-to-treat time to loss of virologic response (ITT-TLOVR) algorithm. Safety, tolerability, adherence, impact of baseline protease mutations on virologic response, and emergence of resistance on therapy were assessed. RESULTS: Demographics were comparable across groups. By intent-to-treat time to loss of virologic response, 166 QD subjects (55.3%) and 155 BID subjects (51.8%) were responders at week 48 (P = 0.413), with similar mean increases in CD4 T-cell count. QD subjects demonstrated better adherence than BID subjects. The occurrence of treatment-related moderate/severe adverse events was comparable for all events except nausea, which was reported more frequently among BID-treated subjects. Emergence of new protease resistance mutations on treatment was similarly infrequent in both groups. CONCLUSION: LPV/r dosed QD resulted in increased treatment adherence and was as efficacious as BID LPV/r while providing similar safety, tolerability, and limited resistance evolution.

Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection.

BACKGROUND: The MERIT (Maraviroc versus Efavirenz in Treatment-Naive Patients) study compared maraviroc and efavirenz, both with zidovudine-lamivudine, in antiretroviral-naive patients with R5 human immunodeficiency virus type 1 (HIV-1) infection. METHODS: Patients screened for R5 HIV-1 were randomized to receive efavirenz (600 mg once daily) or maraviroc (300 mg once or twice daily) with zidovudine-lamivudine. Coprimary end points were proportions of patients with a viral load <400 and <50 copies/mL at week 48; the noninferiority of maraviroc was assessed. RESULTS: The once-daily maraviroc arm was discontinued for not meeting prespecified noninferiority criteria. In the primary 48-week analysis (n = 721), maraviroc was noninferior for <400 copies/mL (70.6% for maraviroc vs 73.1% for efavirenz) but not for <50 copies/mL (65.3% vs 69.3%) at a threshold of -10%. More maraviroc patients discontinued for lack of efficacy (11.9% vs 4.2%), but fewer discontinued for adverse events (4.2% vs 13.6%). In a post hoc reanalysis excluding 107 patients (15%) with non-R5 screening virus by the current, more sensitive tropism assay, the lower bound of the 1-sided 97.5% confidence interval for the difference between treatment groups was above -10% for each end point. CONCLUSIONS: Twice-daily maraviroc was not noninferior to efavirenz at <50 copies/mL in the primary analysis. However, 15% of patients would have been ineligible for inclusion by a more sensitive screening assay. Their retrospective exclusion resulted in similar response rates in both arms Trial registration. ClinicalTrials.gov identifier: (NCT00098293) .

Adenitis infecciosa. Parte 3 / Infectious adenitis. Part 3

Se analizó un grupo de pacientes que concurrieron a los consultorios externos de un hospital de enfermedades infecciosas, presentando como síntoma principal adenopatías regionales o generalizadas. El 78 se hallaban entre los 20 y 40 años de edad, el 56 fue de evolución aguda, predominando netamente la distribución regional, en especial la localización cervical. Se llegó al diagnóstico final en el 80 de los casos. En base a la experiencia realizada, se presenta un algoritmo diagnóstico y se establecen pautas de conducta ante este síndrome (AU)

Adenitis infecciosa. Parte 3 / Infectious adenitis. Part 3

Se analizó un grupo de pacientes que concurrieron a los consultorios externos de un hospital de enfermedades infecciosas, presentando como síntoma principal adenopatías regionales o generalizadas. El 78 se hallaban entre los 20 y 40 años de edad, el 56 fue de evolución aguda, predominando netamente la distribución regional, en especial la localización cervical. Se llegó al diagnóstico final en el 80 de los casos. En base a la experiencia realizada, se presenta un algoritmo diagnóstico y se establecen pautas de conducta ante este síndrome

Actinomicosis bronquial primaria y cuerpo extraño / Primary bronchial actinomycosis and foreign body

This paper presents the fourth case reported on the association of primary bronchial actinomycosis and foreign body. The pathogenesis of this rare association has been linked to the low respiratory tract and a foreign body (chicken bone); it depends on its characteristics and how long it has remained lodged into the bronchial tree. The diagnosis of this case was very difficult and late. Several endoscopy procedures were required in order to detect it. Our patient has been treated successfully with parenteral penicillin in association with an original bronchoscopic procedure using a laser technique to find the foreign body and take it out of the respiratory tract. We consider that it is necessary to remember this association in every patient who suffers from recurrent pneumonia, in those who are at risk of foreign body aspiration and when the presence of an endobronchial mass is suspected.(AU)

Actinomicosis bronquial primaria y cuerpo extraño / Primary bronchial actinomycosis and foreign body

This paper presents the fourth case reported on the association of primary bronchial actinomycosis and foreign body. The pathogenesis of this rare association has been linked to the low respiratory tract and a foreign body (chicken bone); it depends on its characteristics and how long it has remained lodged into the bronchial tree. The diagnosis of this case was very difficult and late. Several endoscopy procedures were required in order to detect it. Our patient has been treated successfully with parenteral penicillin in association with an original bronchoscopic procedure using a laser technique to find the foreign body and take it out of the respiratory tract. We consider that it is necessary to remember this association in every patient who suffers from recurrent pneumonia, in those who are at risk of foreign body aspiration and when the presence of an endobronchial mass is suspected.